Muscarinic receptor antagonists

• US 20040110229A1
• Filed: 04/29/2003
• Published: 06/10/2004
• Est. Priority Date: 02/16/1999
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Moran, Edmund J., Mammen, Mathai, Marquess, Daniel, Griffin, John H., Oare, David, Aggen, James
• Granted Patent: US 7,456,203 B2
• Time in Patent Office: Days
• US Class Current: 435/7.1
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: C07C 211/32 containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
• CPC Class Codes: C07C 2603/32 Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

Disclosed are multibinding compounds which are muscarinic receptor antagonists. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator provided that at least one of said ligand is a muscarinic receptor antagonist. The multibinding compounds of this invention are useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.

Claims

1. A multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers, wherein each of said ligands comprises, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor and pharmaceutically acceptable salts thereof, provided that at least one of said ligands is a muscarinic receptor antagonist, and further provided that when the multibinding compound comprises of 2 or 3 ligands, then only one of the ligands is 11-acetyl-5,11-dihydro-6H-pyrido[2,3b][1,4]-benzodiazepin-6-one, N-methylquinuclidine, or a compound of formula:

2. A multibinding compound of Formula (I):

(L)_p(X)_q  

 

(I)

wherein;

each L is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor;

each X is independently a linker;

p is an integer of from 2 to 10; and

q is an integer of from 1 to 20, and pharmaceutically acceptable salts thereof, provided that at least one of said ligands is a muscarinic receptor antagonist, and further provided that when the multibinding compound comprises of 2 or 3 ligands, then only one of the ligands is 11-acetyl-5,11-dihydro-6H-pyrido[2,3][1,4]benzodiazepin-6-one, N-methylquinuclidine, or a compound of formula;

wherein;

n^a is 0 or 1;

R^c is hydrogen or alkyl;

R^d is hydrogen; and

R^e is —

CO₂CR^f (phenyl)₂ wherein R^f is hydrogen or hydroxy.

3. The multibinding compound of claim 2 wherein q is less than p.

4. The multibinding compound of claim 3 wherein each ligand, L, that is a muscarinic receptor antagonist in the multibinding compound of Formula (I) is independently selected from the group consisting of:

(1) a compound of formula (a);

wherein;

A is an aryl or a heteroaryl ring;

B″

is —

CH₂—

, —

O—

or —

NR^a—

where R^a is hydrogen, alkyl, or substituted alkyl;

R¹ is hydrogen or alkyl;

R² is selected from a group consisting of formula (i), (ii), (iii), or “

Het”

;

wherein;

- - - - - is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —

CH—

, —

O—

, —

S(O)n₃—

(where n₃ is an integer of from 0 to

     2), or —

NR⁴—

(wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);

“

Het”

is a heteroaryl ring which optionally attaches the ligand to a linker;

R³ is hydrogen, alkyl, amino, substituted amino, —

OR^a (where R^a is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker;

R⁵ is hydrogen, alkyl, amino, substituted amino, —

OR^b (where R^b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

K is a bond or an alkylene group;

K″

is a bond, —

C(O)—

, —

S(O)_n4—

(where n₄ is an integer of from 0 to

     2), or an alkylene group optionally substituted with a hydroxyl group; and

B is a heterocycloamino group which optionally attaches the ligand to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “

Het”

, or the heterocycloarnino group attaches the ligand to a linker;

(2) a compound of formula (b);

wherein;

C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

R⁹ is hydrogen, hydroxy, cyano, aminocarbonyl which optionally links the ligand to a linker, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

R¹⁰ is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

Q is a single bond, —

O—

, —

COCH₂—

, —

C(O)NH—

, —

NHC(O)O—

, —

NHC(O)NH—

, or —

C(O)O—

;

Q″

is selected from the group consisting of;

(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker;

(ii) carboxy which optionally links the ligand to a linker;

(iii) a group of formula (iv);

(iv)

where;

E is hydrogen, a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —

O—

, —

S—

, or —

NR^g —

(wherein R^g is hydrogen or alkyl); and

R¹¹ is a group of formula (v), (vi), or “

Het”

;

wherein;

- - - - - is an optional bond;

T and U are, independently of each other, —

O—

or —

CH₂—

;

n₅ is an integer of from 1 to 3; and

“

Het”

is heteroaryl; and

(iv) a group of formula (vii), (viii) or (ix);

wherein;

n₆ is 0 or 1;

M⁻

is a counterion;

R¹² is a covalent bond attaching the ligand to a linker;

R¹³ is alkyl, alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker;

R¹⁴ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R¹⁵ is hydrogen or alkyl and

J is;

provided that at least one of the C, R⁹, R¹⁰, and Q″

attaches the ligand to a linker;

(3) a compound of formula (c);

wherein;

G′

is pyrrolidine, piperidine, or

wherein said G′

groups optionally attach the ligand to a linker;

n₇ is an 0 or 1, provided that when the nitrogen atom of the quinclidine ring attaches the ligand to the linker then n₇ is 0;

n₈ is 1 or 2;

g is an integer of from 0 to 3;

each R¹⁵ is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker;

G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and

G″

is a single bond or an alkylene group provided that at least one of the R¹⁵, G, G′

, and G″

attaches the ligand to a linker;

(4) a compound of formula (d);

wherein;

n₉ is 1 or 2;

n₁₀is 0 or 1 provided that n₉+n₁₀ is 1 or 2;

P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

P″

is a single bond or an alkylene group;

S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker;

(5) a compound of formula (e);

wherein;

n₁₄ is 0, 1, or 2;

n₅₂ is 0 or 1;

R¹⁶ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R¹⁷, R¹⁸, and R¹⁹ are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker;

R²⁰ and R²¹ are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker;

or R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ attaches the ligand to a linker;

or

(6) a compound of formula (f);

wherein;

R²² is hydrogen or halo;

R²³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl;

R²⁴ is hydroxy, halo, or a covalent bond attaching the ligand to a linker;

R²⁵ and R²⁶ are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R²⁵ and R²⁶ together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R²⁴, R²⁵, and R²⁶ attaches the ligand to a linker; and

each ligand, L, that is an allosteric modulator of a muscarinic receptor in the multibinding compound of Formula (I) is independently selected from a group consisting of;

(7) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³², —

N⁺(R³³R³⁴R³⁵) or —

OR³² where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen, alkyl, or aralkyl; and

R³² and R³⁵ represent a covalent bond attaching the ligand to a linker;

R²⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁸ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbarnoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁹ and R³⁰ are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino;

or

one of R²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms a methylenedioxy or ethylenedioxy group;

(8) a compound of formula (h);

wherein;

n₁₁ is an integer of from 1 to 7;

n₁₂ is 0 to 7;

F is —

NR⁴⁰—

, —

O—

, —

S—

, or —

CHR⁴¹—

(wherein R⁴⁰ and R⁴¹ are, independently of each other, hydrogen, alkyl, or substituted alkyl);

F″

is a covalent bond, —

OR⁴³, —

NR⁴²R⁴³ or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker;

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁷ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and

R³⁸ is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R³⁸ and R⁴³ attaches the ligand to a linker;

R³⁹ is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl;

or

(9) a compound of formula (i);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR⁴⁹ where R⁴⁹ is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle;

R⁴⁸ is a covalent bond that attaches the ligand to a linker;

R⁴⁹ is alkyl; and

pharmaceutically acceptable salts, individual isomers, mixture of isomers, and prodrugs thereof provided that at least one of the ligands is a muscarinic receptor antagonist.

5. The multibinding compound of claim 3 wherein each ligand, L, that is a muscarinic receptor antagonist in the multibinding compound of Formula (I) is independently selected from a group consisting of:

(1) a compound of formula (a);

wherein;

A is an aryl or a heteroaryl ring;

R¹ is hydrogen or alkyl;

R² is selected from a group consisting of formula (i), (ii), (iii), or “

Het”

;

wherein;

- - - - - is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —

CH—

, —

O—

, —

S(O)n₃—

(where n₃ is an integer of from 0 to

     2), or —

NR⁴—

(wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);

“

Het”

is a heteroaryl ring which optionally attaches the ligand to a linker;

R³ is hydrogen, alkyl, amino, substituted amino, —

OR^a (where R^a is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker;

R⁵ is hydrogen, alkyl, amino, substituted amino, —

OR^b (where R^b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

K is a bond or an alkylene group;

K″

is a bond, —

C(O)—

, —

S(O)_n4—

(where n₄ is an integer of from 0 to

     2), or an alkylene group optionally substituted with a hydroxyl group; and

B is a heterocycloamino group which optionally attaches the ligand to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “

Het”

, or the heterocycloarnino group attaches the ligand to a linker;

(2) a compound of formula (b);

wherein;

C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

R⁹ is hydrogen, hydroxy, cyano, aminocarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

R¹⁰ is hydrogen, aryl, heteroaryl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

Q is a single bond or —

C(O)O—

such that;

when Q is a bond then, Q″

is a group of formula (iv);

where;

E is hydrogen, a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —

O—

, —

S—

, or —

NR^g—

(wherein R^g is hydrogen or alkyl); and

R¹¹ is a group of formula (v), (vi), or “

Het”

;

wherein;

T and U are, independently of each other, —

O—

or —

CH₂—

;

n₅ is an integer of from 1 to 3; and

“

Het”

is heteroaryl provided that at least one of C, E, R⁹, and R¹⁰ attaches the ligand to a linker; and

when Q is —

C(O)O—

or —

NHC(O)O—

then, Q″

is a group of formula (vii) or (viii);

wherein n₆ is 0 or 1;

M⁻

is a counterion;

R¹² is a covalent bond attaching the ligand to a linker;

R¹³ is alkyl alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker;

R¹⁴ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker; and

J is;

provided that at least one of the C, R⁹, R¹⁰, R¹², R¹³, and R¹⁴ attaches the ligand to a linker;

(3) a compound of formula (c);

wherein;

G′

is pyrrolidine, piperidine, or

wherein M⁻

is a counterion and further

wherein said G′

groups optionally attach the ligand to a linker;

n₇ is an 0 or 1, provided that when the nitrogen atom of the quinclidine ring attaches the ligand to the linker then n₇ is 0;

n_g is 1 or 2;

g is an integer of from 0 to 3;

each R⁵ is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker;

G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and

G″

is a single bond or an alkylene group provided that at least one of the R¹⁵, G, G′

, and G″

attaches the ligand to a linker;

(4) a compound of formula (d);

wherein;

n₉ is 1 or 2;

n₁₀ is 0 or 1 provided that n₉+n₁₀ are 1 or 2;

P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

P″

is a single bond or an alkylene group;

S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker;

(5) a compound of formula (e);

wherein;

R¹⁶ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R¹⁷, R¹⁸, and R¹⁹ are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker;

R²⁰ and R²¹ are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker;

or R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ attaches the ligand to a linker;

or

(6) a compound of formula (f);

wherein;

R²² is hydrogen or halo;

R²³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl;

R²⁴ is hydroxy, halo, or a covalent bond attaching the ligand to a linker;

R²⁵ and R²⁶ are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R²⁵ and R²⁶ together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R²⁴, R²⁵, and R²⁶ attaches the ligand to a linker;

each ligand, L, that is an allosteric modulator of a muscarinic receptor is independently selected from a group consisting of;

(7) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³², —

N⁺(R³³R³⁴R³⁵) or —

OR³² where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen, alkyl, or aralkyl; and

R³² and R³⁵ represent a covalent bond attaching the ligand to a linker;

R²⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁸ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁹ and R³⁰ are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino;

or

one of R²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms a methylenedioxy or ethylenedioxy group; and

(8) a compound of formula (h);

wherein;

n₁₁ is an integer of from 1 to 7;

n₁₂ is an integer of from 0 to 7;

F is —

NR⁴⁰—

, —

O—

, —

S—

, or —

CHR⁴¹—

(wherein R⁴⁰ and R⁴¹ are, independently of each other, hydrogen or alkyl);

F″

is a covalent bond, —

OR⁴³, —

NR⁴²R⁴³, or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein ⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker;

R³⁶ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and

R³⁸ is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R³⁸ and R⁴³ attaches the ligand to a linker; and

each linker independently has the formula;

—

X^a—

Z—

(Y^a—

Z)_m—

Y^b—

Z—

X^a—

wherein;

m is an integer of from 0 to 20;

X^a at each separate occurrence is selected from the group consisting of —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR—

, —

C(S), —

C(S)O—

, —

C(S)NR—

or a covalent bond where R is as defined below;

Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^a and Y^b at each separate occurrence are selected from the group consisting of —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

NR—

, —

S(O)n—

, —

C(O)NR′

—

, —

NR′

C(O)—

, —

NR′

C(O)NR′

—

, —

NR′

C(S)NR′

—

, —

C(═

NR′

)—

NR′

—

, —

NR′

—

C(═

NR′

)—

, —

OC(O)—

NR′

—

, —

NR′

—

C(O)—

O—

, —

N═

C(X^a)—

NR′

—

, —

NR′

—

C(X^a)═

N—

, —

P(O)(OR′

)—

O—

, —

O—

P(O)(OR′

)—

, —

S(O)_nCR′

R″

—

, —

S(O)_n—

NR′

—

, —

NR′

—

S(O)_n—

, —

S—

S—

, and a covalent bond;

where n is 0, 1 or 2; and

R, R′ and

R″

at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.

6. The multibinding compound of claim 5 wherein p is 2 and q is 1.

7. A bivalent multibinding compound of formula:

L^a—

X—

L^b

where;

L^a is a muscarinic receptor antagonist and is selected from the group consisting of;

(1) a compound of formula (a);

wherein;

A is an aryl or a heteroaryl ring;

B″

is —

CH₂—

, —

O—

or —

NR^a—

where R^a is hydrogen, alkyl, or substituted alkyl;

R¹ is hydrogen or alkyl;

R² is selected from a group consisting of formula (i), (ii), (iii), or “

Het”

;

wherein;

- - - - - is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —

CH—

, —

O—

, —

S(O)n₃—

(where n₃ is an integer of from 0 to

     2), or —

NR⁴—

(wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);

“

Het”

is a heteroaryl ring which optionally attaches the ligand to a linker;

R³ is hydrogen, alkyl, amino, substituted amino, —

OR^a (where R^a is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker;

R⁵ is hydrogen, alkyl, amino, substituted amino, —

OR^b (where R^b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

K is a bond or an alkylene group;

K″

is a bond, —

C(O)—

, —

S(O)_n4—

(where n₄ is an integer of from 0 to

     2), or an alkylene group optionally substituted with a hydroxyl group; and

B is a heterocycloamino group which optionally attaches the ligand to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “

Het”

, or the heterocycloamino group attaches the ligand to a linker; and

(2) a compound of formula (b);

wherein;

C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

R⁹ is hydrogen, hydroxy, cyano, aminocarbonyl which optionally links the ligand to a linker, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

R¹⁰ is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

Q is a single bond, —

O—

, —

COCH₂—

, —

C(O)NH—

, —

NHC(O)O—

, —

NHC(O)NH—

, or —

C(O)O—

;

Q″

is selected from the group consisting of;

(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker;

(ii) carboxy which optionally links the ligand to a linker;

(iii) a group of formula (iv);

where;

E is hydrogen, a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —

O—

, —

S—

, or —

NR^g —

(wherein R^g is hydrogen or alkyl); and

R¹¹ is a group of formula (v), (vi), or “

Het”

;

wherein;

- - - - - is an optional bond;

T and U are, independently of each other, —

O—

or —

CH₂—

;

n₅ is an integer of from 1 to 3; and

“

Het”

is heteroaryl; and

(iv) a group of formula (vii), (viii) or (ix);

wherein;

n₆ is 0 or 1;

M⁻

is a counterion;

R¹² is a covalent bond attaching the ligand to a linker;

R¹³ is alkyl, alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker;

R¹⁴ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R⁵¹ is hydrogen or alkyl; and

J is;

provided that at least one of the C, R⁹, R¹⁰, and Q″

attaches the ligand to a linker;

L^b is an allosteric modulator of a muscarinic receptor and is selected from a group consisting of;

(3) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³², —

N⁺(R³³R³⁴R³⁵) or —

OR³² where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen, alkyl, or aralkyl; and

R³² and R³⁵ represent a covalent bond attaching the ligand to a linker;

R²⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁸ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁹ and R³⁰ are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino;

or

one of R²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms a methylenedioxy or ethylenedioxy group;

(4) a compound of formula (h);

wherein;

n₁₁ is an integer of from 1 to 7;

n₁₂ is 0 to 7;

F is NR⁴⁰—

, —

O—

, —

S—

, or —

CHR⁴¹—

(wherein R⁴⁰ and R⁴¹ are, independently of each other, hydrogen, alkyl, or substituted alkyl);

F″

is a covalent bond, —

OR⁴³, —

NR⁴²R⁴³, or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker;

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁷ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁸ is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R³⁸ and R⁴³ attaches the ligand to a linker; and

R³⁹ is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and

(5) a compound of formula (i);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR⁴⁹ where R⁴⁹ is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle;

R⁴⁸ is a covalent bond that attaches the ligand to a linker;

R⁴⁹ is alkyl; and

X is a compound of formula;

—

X^a—

Z—

(Y^a—

Z)_m—

Y^b—

Z—

X^a—

wherein;

m is an integer of from 0 to 20;

X^a at each separate occurrence is selected from the group consisting of —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR—

, —

C(S), —

C(S)O—

, —

C(S)NR—

or a covalent bond where R is as defined below;

Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^a and Y^b at each separate occurrence are selected from the group consisting of —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

NR—

, —

S(O)n—

, —

C(O)NR′

—

, —

NR′

C(O)—

, —

NR′

C(O)NR′

—

, —

NR′

C(S)NR′

—

, —

C(═

NR′

)—

NR′

—

, —

NR′

—

C(═

NR′

)—

, —

OC(O)—

NR′

—

, —

NR′

C(O)—

O—

, —

N═

C(X^a)—

NR′

—

, —

NR′

—

C(X^a)═

N—

,—

P(O)(OR′

)—

O—

, —

O—

P(O)(OR′

)—

, —

S(O)_nCR′

R″

—

, —

S(O)_n—

NR′

—

, —

NR′

—

S(O)_n—

, —

S—

S—

, and a covalent bond;

where n is 0, 1 or 2; and

R, R′ and

R″

at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic; and

pharmaceutically acceptable salts, individual isomers, mixture of isomers, and prodrugs thereof.

8. The multibinding compound of claim 7 wherein:

L^a is a compound of formula (a);

wherein;

A is an phenyl;

B″

is —

CH₂—

, —

O—

or —

NH—

;

R¹ is hydrogen;

R² is;

where R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

K and K″

are a bond; and

B is;

(i) pyrrolidine, piperidine, 4-methylpiperidine, or hexahydroazepine where the nitrogen atom in said rings attaches the ligand to a linker;

L^b is selected from a group consisting of;

(1) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³² or —

N⁺(R³³R³⁴R³⁵) where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen or alkyl; and

R³² and R³⁵ represent a covalent bond attaching the ligand to a linker;

(2) a compound of formula (h);

wherein;

n₁₂ is 2 to 7;

F″

is —

NR⁴²R⁴³ or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker; and

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, amino, or substituted amino; and

(3) a compound of formula (i);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR⁴⁹ where R⁴⁹ is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle;

R⁴⁸ is a covalent bond that attaches the ligand to a linker;

R⁴⁹ is alkyl.

9. The multibinding compound of claim 8 wherein L^a is selected from the group consisting of:

10. The multibinding compound of claim 8 wherein L^b is selected from the group consisting of:

11. The multibinding compound of claim 8 wherein X is selected from the group consisting of:

12. The multibinding compound of claim 7 wherein:

L^a is a compound of formula (b);

wherein;

C is an aryl or heteroaryl ring;

R⁹ is hydrogen, hydroxy, aminocarbonyl which optionally links the ligand to a linker via the amino group, alkyl optionally substituted with one, two or three substituents selected from hydroxy, carboxy, alkoxycarbonyl, amino, and substituted amino, or R⁹ is a covalent bond attaching the ligand to a linker;

R¹⁰ is hydrogen, aryl, or cycloalkyl;

Q is a single bond, —

O—

, —

COCH₂—

, —

C(O)NH—

, —

NHC(O)O—

, —

NHC(O)NH—

, or —

C(O)O—

;

Q″

is selected from the group consisting of;

(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker;

(ii) carboxy which optionally links the ligand to a linker;

(iii) a group of formula (iv);

where;

E is a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is alkylene; and

R¹¹ is;

and

(iv) a group of formula;

wherein;

n₆ is 0 or 1;

R¹⁴ is a covalent bond attaching the ligand to a linker;

R⁵¹ is hydrogen or alkyl; and

J is —

(CH₂)₂—

;

provided that at least one of the R⁹ and Q″

group attaches the ligand to a linker;

L^b is selected from a group consisting of;

(1) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³² or —

N⁺(R³³R³⁴R³⁵) where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen or alkyl; and

R³² and R³⁵ represent a covalent bond attaching the ligand to a linker;

(2) a compound of formula (h);

wherein;

n₁₂ is 2 to 7;

F″

is —

NR⁴²R⁴³ or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker; and

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, amino, or substituted amino; and

(3) a compound of formula (i);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR49 where R49 is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle;

R⁴⁸ is a covalent bond that attaches the ligand to a linker; and

R⁴⁹ is alkyl.

13. The multibinding compound of claim 12 wherein:

L^a is a compound of formula (b);

wherein;

C is phenyl, 2-hydroxy-5-methylphenyl, or pyridine;

R⁹ is hydrogen, hydroxy, aminocarbonyl which optionally links the ligand to a linker via the amino group, or hydroxymethyl;

R¹⁰ is hydrogen, phenyl, cyclopentyl, or cyclohexyl;

Q is a single bond, —

O—

, —

COCH₂—

, —

C(O)NH—

, —

NHC(O)O—

, —

NHC(O)NH—

, or —

C(O)O—

;

Q″

is selected from the group consisting of;

(i) 2-N-methylaminoethyl, 2-N-ethylaminoethyl, 3-methylaminobutyl, 2-N-isopropylaminoethyl, 4-ethylaminobutyn-1-yl, or 5-N-ethylamino-2-methylpentyn-2-yl wherein the nitrogen atom of the amino group links the ligand to a linker;

(ii) carboxy which links the ligand to a linker;

(iii) a group of formula (iv);

where;

E is a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is —

CH₂—

; and

R¹¹ is;

and

(iv) a group of formula;

wherein;

n₆ is 0 or 1;

R¹⁴ is a covalent bond attaching the ligand to a linker;

R⁵¹ is hydrogen or methyl; and

J is —

(CH₂)₂—

;

provided that at least one of the R⁹ and Q″

group attaches the ligand to a linker;

L^b is an allosteric modulator of a muscarinic receptor and is selected from a group consisting of;

(1) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³² or —

N⁺(R³³R³⁴R³⁵) where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen or alkyl; and

R³² and R³⁵represent a covalent bond attaching the ligand to a linker;

(4) a compound of formula (h);

wherein;

n₁₂ is 2 to 7;

F″

is —

NR⁴²R⁴³ or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker; and

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, amino, or substituted amino; and

(5) a compound of formula (i);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR⁴⁹ where R⁴⁹ is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle;

R⁴⁸ is a covalent bond that attaches the ligand to a linker;

R⁴⁹ is alkyl.

14. The multibinding compound of claim 13 wherein L^a is selected from the group consisting of:

15. The multibinding compound of claim 13 wherein:

L^b is selected from the group consisting of;

wherein the nitrogen atom of the secondary aliphatic amino group is attached to a linker via a covalent bond and is optionally substituted with a methyl group to form a quaternary ammonium salt.

16. The multibinding compound of claim 13 wherein X is selected from the group consisting of:

21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of claim 7.

23. A method for treating diseases mediated by a muscarinic receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multibinding compound of claim 7.

17. A multibinding compound of formula:

L^a—

X—

L^{a ′}

wherein L^a and L^a′

is a muscarinic receptor antagonist and is independently selected from a group consisting of;

(1) a compound of formula (a);

wherein;

A is an aryl or a heteroaryl ring;

B″

is —

CH₂—

, —

O—

or —

NR^a—

where R^a is hydrogen, alkyl, or substituted alkyl;

R¹ is hydrogen or alkyl;

R² is selected from a group consisting of formula (i), (ii), (iii), or “

Het”

;

wherein;

- - - - - is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —

CH—

, —

O—

, —

S(O)n₃—

(where n₃ is an integer of from 0 to

     2), or —

NR⁴—

(wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);

“

Het”

is a heteroaryl ring which optionally attaches the ligand to a linker;

R³ is hydrogen, alkyl, amino, substituted amino, —

OR^a (where R^a is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker;

R⁵ is hydrogen, alkyl, amino, substituted amino, —

OR^b (where R^b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

K is a bond or an alkylene group;

K″

is a bond, —

C(O)—

, —

S(O)_n4—

(where n₄ is an integer of from 0 to

     2), or an alkylene group optionally substituted with a hydroxyl group; and

B is a heterocycloamino group which optionally attaches the ligand to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “

Het”

, or the heterocycloarnino group attaches the ligand to a linker;

(2) a compound of formula (b);

wherein;

C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

R⁹ is hydrogen, hydroxy, cyano, aminocarbonyl which optionally links the ligand to a linker, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

R¹⁰ is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

Q is a single bond, —

O—

, —

COCH₂—

, —

C(O)NH—

, —

NHC(O)O—

, —

NHC(O)NH—

, or —

C(O)O—

;

Q″

is selected from the group consisting of;

(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker;

(ii) carboxy which optionally links the ligand to a linker;

(iii) a group of formula (iv);

where;

E is hydrogen, a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —

O—

, —

S—

, or —

NR^g—

(wherein R^g is hydrogen or alkyl); and

R¹¹ is a group of formula (v), (vi), or “

Het”

;

wherein;

- - - - - is an optional bond;

T and U are, independently of each other, —

O—

or —

CH ₂—

;

n₅ is an integer of from 1 to 3; and

“

Het”

is heteroaryl; and

(iv) a group of formula (vii), (viii) or (ix);

wherein;

n₆ is 0 or 1;

M⁻

is a counterion;

R¹² is a covalent bond attaching the ligand to a linker;

R¹³ is alkyl, alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker;

R¹⁴ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R⁵¹ is hydrogen or alkyl; and

J is;

provided that at least one of the C, R⁹, R¹⁰, and Q″

attaches the ligand to a linker;

(3) a compound of formula (c);

wherein;

G′

is pyrrolidine, piperidine, or

wherein said G′

groups optionally attach the ligand to a linker;

n₇ is an 0 or 1, provided that when the nitrogen atom of the quinclidine ring attaches the ligand to the linker then n₇ is 0;

n₈ is 1 or 2;

g is an integer of from 0 to 3;

each R¹⁵ is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker;

G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and

G″

is a single bond or an alkylene group provided that at least one of the R¹⁵, G, G′

, and G″

attaches the ligand to a linker;

(4) a compound of formula (d);

wherein;

n₉ is 1 or 2;

n₁₀ is 0 or 1 provided that n₉+n₁₀ is 1 or 2;

P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

P″

is a single bond or an alkylene group;

S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker;

(5) a compound of formula (e);

wherein;

n₁₄ is 0, 1, or 2;

n₅₂ is 0 or 1;

R¹⁶ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R¹⁷, R¹⁸, and R¹⁹ are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker;

R²⁰ and R²¹ are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker;

or R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ attaches the ligand to a linker;

or

(6) a compound of formula (f);

wherein;

R²² is hydrogen or halo;

R²³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl;

R²⁴ is hydroxy, halo, or a covalent bond attaching the ligand to a linker;

R²⁵ and R²⁶ are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R²⁵ and R²⁶ together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R²⁴, R²⁵, and R²⁶ attaches the ligand to a linker; and

X is a compound of formula;

—

Z^a—

Z—

(Y^a—

Z)_m—

Y^b—

Z—

X^a —

wherein;

m is an integer of from 0 to 20;

X^a at each separate occurrence is selected from the group consisting of —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR—

, —

C(S), —

C(S)O—

, —

C(S)NR—

or a covalent bond where R is as defined below;

Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^a and Y^b at each separate occurrence are selected from the group consisting of —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

NR—

, —

S(O)n—

, —

C(O)NR′

—

, —

NR′

C(O)—

, —

NR′

C(O)NR′

—

, —

NR′

C(S)NR′

—

, —

C(═

NR′

)—

NR′

—

, —

NR′

—

C(═

NR′

)—

, —

OC(O)—

NR′

—

, —

NR′

—

C(O)—

O—

, —

N═

C(X^a)—

NR′

—

, —

NR′

—

C(X^a)═

N—

, —

P(O)(OR′

)—

, —

S(O)_nCR′

R″

—

, —

S(O)_n—

NR′

—

, —

NR′

—

S(O)_n—

, —

S—

S—

, and a covalent bond;

where n is 0, 1 or 2; and

R, R′ and

R″

at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic; and

pharmaceutically acceptable salts, individual isomers, mixture of isomers, and prodrugs thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of Formula (I):

(L)_p(X)_q  

 

(I)

wherein;

each L is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor;

each X is independently a linker;

p is an integer of from 2 to 10; and

q is an integer of from 1 to 20, and pharmaceutically acceptable salts thereof provided that at least one of said ligands is a muscarinic receptor antagonist.

19. The pharmaceutical composition of claim 18 wherein each ligand that is a muscarinic receptor antagonist is independently selected from a group consisting of:

(1) a compound of formula (a);

wherein;

A is an aryl or a heteroaryl ring;

B″

is —

CH₂—

, —

O—

or —

NR^a —

where R^a is hydrogen, alkyl, or substituted alkyl;

R¹ is hydrogen or alkyl;

R² is selected from a group consisting of formula (i), (ii), (iii), or “

Het”

;

wherein;

- - - - - is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —

CH—

, —

O—

, —

S(O)n₃—

(where n₃ is an integer of from 0 to

     2), or —

NR⁴—

(wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);

“

Het”

is a heteroaryl ring which optionally attaches the ligand to a linker;

R³ is hydrogen, alkyl, amino, substituted amino, —

OR^a (where R^a is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker;

R⁵ is hydrogen, alkyl, amino, substituted amino, —

OR^b (where R^b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

K is a bond or an alkylene group;

K″

is a bond, —

C(O)—

, —

S(O)_n4—

(where n₄ is an integer of from 0 to

     2), or an alkylene group optionally substituted with a hydroxyl group; and

B is a heterocycloarnino group which optionally attaches the ligand to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “

Het”

, or the heterocycloamino group attaches the ligand to a linker;

(2) a compound of formula (b);

wherein;

C is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

R⁹ is hydrogen, hydroxy, cyano, aminocarbonyl which optionally links the ligand to a linker, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

R¹⁰ is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker;

Q is a single bond, —

O—

, —

COCH₂—

, —

C(O)NH—

, —

NHC(O)O—

, —

NHC(O)NH—

, or —

C(O)O—

;

Q″

is selected from the group consisting of;

(i) monoaalkylaminoalkyl, monoalkylaminoalkenyl, monoalkylaminoalkynyl wherein the amino group optionally links the ligand to a linker;

(ii) carboxy which optionally links the ligand to a linker;

(iii) a group of formula (iv);

where;

E is hydrogen, a covalent bond attaching the ligand to a linker, or —

CH₂—

W—

R¹¹ wherein W is a single bond or alkylene wherein one of the carbon atoms may optionally be replaced by —

O—

, —

S—

, or —

NR^g—

(wherein R^g is hydrogen or alkyl); and

R¹¹ is a group of formula (v), (vi), or “

Het”

;

wherein;

- - - - - is an optional bond;

T and U are, independently of each other, —

O—

or —

CH₂—

;

n₅ is an integer of from 1 to 3; and

“

Het”

is heteroaryl; and

(iv) a group of formula (vii), (viii) or (ix);

wherein;

n₆ is 0 or 1;

M⁻

is a counterion;

R¹² is a covalent bond attaching the ligand to a linker;

R¹³ is alkyl, alkenyl, cycloalkyl, or a covalent bond attaching the ligand to a linker;

R¹⁴ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R⁵¹ is hydrogen or alkyl; and

J is;

provided that at least one of the C, R⁹, R¹⁰, and Q″

attaches the ligand to a linker;

(3) a compound of formula (c);

wherein;

G′

is pyrrolidine, piperidine, or

wherein said G′

groups optionally attach the ligand to a linker;

n₇ is an 0 or 1, provided that when the nitrogen atom of the quinuclidine ring attaches the ligand to the linker then n₇ is 0;

n₈ is 1 or 2;

g is an integer of from 0 to 3.

each R¹⁵ is, independently of each other, hydrogen, halogen, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, methylenedioxy, ethylenedioxy, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino, or a covalent bond attaching the ligand to a linker;

G is aryl, heteroaryl, heterocyclyl, or cycloalkyl which optionally attach the ligand to a linker; and

G″

is a single-bond or an alkylene group provided that at least one of the R¹⁵, G, G′

, and G″

attaches the ligand to a linker;

(4) a compound of formula (d);

wherein;

n₉ is 1 or 2;

n₁₀ is 0 or 1 provided that n₉+n₁₀ is 1 or 2;

P is an aryl or heteroaryl ring which optionally attaches the ligand to a linker;

P″

is a single bond or an alkylene group;

S is a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the P and S attaches the ligand to a linker;

(5) a compound of formula (e);

wherein;

n₁₄ is 0, 1, or 2;

n₅₂ is 0 or 1;

R¹⁶ is hydrogen, alkyl, or a covalent bond attaching the ligand to a linker;

R¹⁷, R¹⁸, and R¹⁹ are, independently of each other, hydrogen, alkyl, alkoxy, hydroxy, carbamoyl, sulfanoyl, halo, or a covalent bond attaching the ligand to a linker;

R²⁰ and R²¹ are, independently of each other, hydrogen, alkyl or a covalent bond attaching the ligand to a linker;

or R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino ring which optionally attaches the ligand to a linker provided that at least one of the R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ attaches the ligand to a linker;

or

(6) a compound of formula (f);

wherein;

R²² is hydrogen or halo;

R²³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocyclylalkyl;

R²⁴ is hydroxy, halo, or a covalent bond attaching the ligand to a linker;

R²⁵ and R²⁶ are, independently of each other, hydrogen, alkyl, aralkyl, or a covalent bond attaching the ligand to a linker, or R²⁵ and R²⁶ together with the nitrogen atom to which they are attached form a heterocycloamino group which optionally attaches the ligand to a linker provided that at least one of the R²⁴, R²⁵, and R²⁶ attaches the ligand to a linker; and

each ligand, L, that is an allosteric modulator of a muscarinic receptor in the multibinding compound of Formula (I) is independently selected from a group consisting of;

(7) a compound of formula (g);

wherein;

D″

is alkylene;

D is —

NR³¹R³², —

N⁺(R³³R³⁴R³⁵) or —

OR³² where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen, alkyl, or aralkyl; and

R³² and R³⁵ represent a covalent bond attaching the ligand to a linker;

R²⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁸ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁹ and R³⁰ are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono-or dialkylamino;

or

one of R²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms a methylenedioxy or ethylenedioxy group;

(8) a compound of formula (h);

wherein;

n₁₁ is an integer of from 1 to 7;

n₁₂ is 0 to 7;

F is —

NR⁴⁰—

, —

O—

, —

S—

, or —

CHR⁴¹—

(wherein R⁴⁰ and R⁴¹ are, independently of each other, hydrogen, alkyl, or substituted alkyl);

F″

is a covalent bond, —

OR⁴³, —

NR⁴²R⁴³ or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is a covalent bond attaching the ligand to a linker;

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁷ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁸ is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R³⁸ and R⁴³ attaches the ligand to a linker; and

R³⁹ is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and

(9) a compound of formula (i);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR⁴⁹ where R⁴⁹ is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle;

R⁴⁸ is a covalent bond that attaches the ligand to a linker;

R⁴⁹ is alkyl;

each X is independently of each other a compound of formula;

—

X^a—

Z—

(Y^a—

Z)_m—

Y^b—

Z—

X^a—

wherein;

m is an integer of from 0 to 20;

X^a at each separate occurrence is selected from the group consisting of —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR—

, —

C(S), —

C(S)O—

, —

C(S)NR—

or a covalent bond where R is as defined below;

Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^a and Y^b at each separate occurrence are selected from the group consisting of —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

NR—

, —

S(O)n—

, —

C(O)NR′

—

, —

NR′

C(O)—

, —

NR′

C(O)NR′

—

, —

NR′

C(S)NR′

—

, —

C(═

NR′

)—

NR′

—

, —

NR′

C(═

NR′

)—

, —

OC(O)—

NR′

—

, —

NR′

—

C(O)—

O—

, —

N═

C(X^a)—

NR′

—

, —

NR′

—

C(X^a)═

N—

,—

P(O)(OR′

)—

O—

, —

O—

P(O)(OR′

)—

, —

S(O)_nCR′

R″

—

, —

S(O)_n—

NR′

—

, —

NR′

—

S(O)_n—

, —

S—

S—

, and a covalent bond;

where n is 0, 1 or 2; and

R, R′ and

R″

at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic; and

pharmaceutically acceptable salts, individual isomers, mixture of isomers, and prodrugs thereof provided that at least one of the ligands is a muscarinic receptor antagonist.

20. The pharmaceutical composition of claim 19 wherein p is 2 and q is 1.

22. A method for treating diseases mediated by a muscarinic receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers, wherein each of said ligands, comprises, independently of each other, a muscarinic receptor antagonist or an allosteric modulator of a muscarinic receptor provided that at least one of said ligands is a muscarinic receptor antagonist, and pharmaceutically acceptable salts thereof.

24. A method for identifying multimeric ligand compounds possessing multibinding properties for a muscarinic receptor which method comprises:

(a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality;

(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;

(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and

(d) assaying the multimeric ligand compounds produced in the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties for a muscarinic receptor.

26. The method according to claim 24 or 25 wherein the preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b).

27. The method according to claim 26 wherein the multimeric ligand compounds comprising the multimeric ligand compound library are dimeric.

28. The method according to claim 27 wherein the dimeric ligand compounds comprising the dimeric ligand compound library are heterodimeric.

29. The method according to claim 28 wherein the heterodimeric ligand compound library is prepared by sequential addition of a first and second ligand.

30. The method according to claim 24 or 25 wherein, prior to procedure (d), each member of the multimeric ligand compound library is isolated from the library.

31. The method according to claim 30 wherein each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).

32. The method according to claim 24 or 25 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and amphiphilic linkers.

33. The method according to claim 32 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.

34. The method according to claim 33 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å

.

35. The method according to claim 24 or 25 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.

36. The method according to claim 35 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.

37. The method according to claim 24 or 25 wherein the multimeric ligand compound library comprises homomeric ligand compounds.

38. The method according to claim 24 or 25 wherein the multimeric ligand compound library comprises heteromeric ligand compounds.

25. A method for identifying multimeric ligand compounds possessing multibinding properties for a muscarinic receptor which method comprises:

(a) identifying a library of ligands wherein each ligand contains at least one reactive functionality;

(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;

(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and

(d) assaying the multimeric ligand compounds produced in the library prepared in (c) above to identify multimeric ligand compounds possessing multibinding properties for a muscarinic receptor.

39. A library of multimeric ligand compounds which may possess multivalent properties for a muscarinic receptor which library is prepared by the method comprising:

(a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality;

(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and

(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.

41. The library according to claim 39 or 40 wherein the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability and amphiphilic linkers.

42. The library according to claim 41 wherein the linkers comprise linkers of different chain length and/or having different complementary reactive groups.

43. The library according to claim 42 wherein the linkers are selected to have different linker lengths ranging from about 2 to 100 Å

.

44. The library according to claim 39 or 40 wherein the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.

45. The library according to claim 44 wherein said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof wherein the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.

47. The library according to claim 39 or 40 wherein the multimeric ligand compound library comprises heteromeric ligand compounds.

40. A library of multimeric ligand compounds which may possess multivalent properties for a muscarinic receptor which library is prepared by the method comprising:

(a) identifying a library of ligands wherein each ligand contains at least one reactive functionality;

(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and

(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.

46. The library according to claim 40 or 41 wherein the multimeric ligand compound library comprises homomeric ligand compounds.

48. An iterative method for identifying multimeric ligand compounds possessing multibinding properties for a muscarinic receptor which method comprises:

(a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands;

(b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties for a muscarinic receptor;

(c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties for a muscarinic receptor;

(d) evaluating what molecular constraints imparted multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)-(c) above;

(e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration;

(f) evaluating what molecular constraints imparted enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above;

(g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.

49. The method according to claim 48 wherein steps (e) and (f) are repeated from 2-50 times.

50. The method according to claim 49 wherein steps (e) and (f) are repeated from 5-50 times.