NICOTINIC DESENSITIZERS AND METHODS OF SELECTING, TESTING, AND USING THEM

• US 20100129291A1
• Filed: 07/18/2007
• Published: 05/27/2010
• Est. Priority Date: 07/18/2006
• Status: Active Grant

• Current Assignee: Potomac Pharmaceuticals Incorporated
• Original Assignee: Bethesda Pharmacology Associates
• Inventors: Kellar, Kenneth J., Xiao, Yingxian
• Granted Patent: US 8,642,612 B2
• Time in Patent Office: Days
• US Class Current: 424/9.200
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/18 Bridged systems
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 33/9406 Neurotransmitters
• CPC Class Codes: G01N 33/944 Acetylcholine

Abstract

The present invention discloses nicotinic desensitizers and methods of selecting, testing, and using them. The present invention provides methods for selecting nicotinic desensitizers from one or more compounds by using receptor, cell, and tissue models; and methods for testing one or more nicotinic desensitizers for their therapeutic utility by using animal models. The present invention also provides compounds of formula (I) and (II) as nicotinic desensitizers. Nicotinic desensitizers of the present invention are useful for the treatment of a wide range of conditions, diseases, and disorders.

Claims

1. A method for treating, preventing, or reversing one or more conditions or diseases associated with aging, addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer'"'"'s disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson'"'"'s disease, Huntington'"'"'s disease, Tourette'"'"'s syndrome, amyotrophic lateral sclerosis, inflammation, stoke and spinal-cord injury in a patient suffering said one or more conditions or diseases comprising administering to the patient a therapeutically effective amount of at least one nicotinic desensitizer, or pharmaceutically acceptable salt, solvate, and/or ester thereof.

2. The method of claim 1, wherein the at least one nicotinic desensitizer is a compound

(1) the binding affinity (k_d or K_i) of which to a nAChR subtype is less than about 1,000 nM;

(2) the agonist activity (E_max) of which for the nAChR subtype is less than about 10% of the E_max of a typical nicotinic agonist for the nAChR subtype; and

(3) the inhibition of which to receptor activation of the nAChR subtype by the typical nicotinic agonist (IC_50(A)) is more than about 1,000 nM when the compound is applied to the nAChR subtype simultaneously with the typical agonist.

3. The method of claim 1, wherein the at least one nicotinic desensitizer is a compound

(1) the agonist activity (E_ax) of which for a nAChR subtype is less than about 10% of the E_max of a typical nicotinic agonist for the nAChR subtype;

(2) the inhibition of which to receptor activation of the nAChR subtype by the typical nicotinic agonist via desensitization (IC_50(D)) is less than about 10,000 nM;

(3) the inhibition of which to receptor activation of the nAChR subtype by a typical nicotinic agonist (IC_50(A)) is more than about 1,000 nM when the compound is applied to the nAChR subtype simultaneously with the typical agonist; and

(4) the IC_50(D)<

the IC_50(A);

wherein the desensitization comprises contacting the compound with the nAChR subtype for a period of time before the typical nicotinic agonist is applied to the nAChR subtype.

4. The method of claim 1, wherein the at least one nicotinic desensitizer is a compound of formula (I):

or a pharmaceutically acceptable tautomer, salt, solvate, and/or ester thereof, wherein,

L is O, S, or NR^S;

Het is heterocyclyl;

each R¹, R², R³, and R⁴, is independently H, halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, hydroxyl, alkoxy, or an optionally substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, N-alkyl amino, N,N-dialkyl amino, —

NH—

C(O)—

R⁶, —

NH—

C(O)—

OR⁶, —

O—

C(O)—

R⁶, —

O—

C(O)—

OR⁶, nitro, and alkoxy;

R⁵ is H, or an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; and

R⁶ is an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, or heteroaryl.

5. The method of claim 1, wherein the at least one nicotinic desensitizer is a compound of formula (II):

or a pharmaceutically acceptable tautomer, salt, solvate, and/or ester thereof, wherein,

R¹, R², and R³ are each independently H, halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, hydroxyl, alkoxy, or an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, nitro, and alkoxy; and

R⁵ is H, an optionally substituted C₁-C₆ alky, C₂-C₆ alkenyl, or C₂-C₁₀ alkynyl;

wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, nitro, and alkoxy.

6. The method of claim 2, wherein the typical nicotinic agonist is acetylcholine or nicotine.

7. The method of claim 3, wherein the typical nicotinic agonist is acetylcholine or nicotine.

8. The method of claim 1, further comprising co-administering at least one additional active agent.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one nicotinic desensitizer, or a pharmaceutically acceptable salt, solvate, and/or ester thereof;

and a pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition of claim 9, wherein the at least one nicotinic desensitizer is a compound

(1) the binding affinity (K_d or K_i) of which to a nAChR subtype is less than about 1,000 nM;

(2) the agonist activity (E_max) of which for the nAChR subtype is less than about 10% of the E_max of a typical nicotinic agonist for the nAChR subtype; and

(3) the inhibition of which to receptor activation of the nAChR subtype by the typical nicotinic agonist (IC_50(A)) is more than about 1,000 nM when the compound is applied to the nAChR subtype simultaneously with the typical agonist.

11. The pharmaceutical composition of claim 9, wherein the at least one nicotinic desensitizer is a compound

(1) the agonist activity (E_max) of which for a nAChR subtype is less than about 10% of the E_max of a typical nicotinic agonist for the nAChR subtype;

(2) the inhibition of which to receptor activation of the nAChR subtype by the typical nicotinic agonist via desensitization (IC_50(D)) is less than about 10,000 nM;

(3) the inhibition of which to receptor activation of the nAChR subtype by a typical nicotinic agonist (IC_50(A)) is more than about 1,000 nM when the compound is applied to the nAChR subtype simultaneously with the typical agonist; and

(4) the IC_50(A)<

the IC_50(A);

wherein the desensitization comprises contacting the compound with the nAChR subtype for a period of time before the typical nicotinic agonist is applied to the nAChR subtype.

12. The pharmaceutical composition of claim 9, wherein the at least one nicotinic desensitizer is a compound of formula (1):

or a pharmaceutically acceptable tautomer, salt, solvate, and/or ester thereof, wherein,

L is O, S, or NR⁵;

Het is heterocyclyl;

each R¹, R², R³, and R⁴, is independently H, halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, hydroxyl, alkoxy, or an optionally substituted C_I-C₁₂ alkyl, C₂-C₁₂ alkenyl, or C₂-C₁₂ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, N-alkyl amino, N,N-dialkyl amino, —

NH—

C(O)—

R⁶, —

NH—

C(O)—

OR⁶, —

O—

C(O)—

R⁶, —

O—

C(O)—

OR⁶, nitro, and alkoxy;

R⁵ is H, or an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; and

R⁶ is an optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, or heteroaryl.

13. The pharmaceutical composition of claim 9, wherein the at least one nicotinic desensitizer is a compound of formula (II):

or a pharmaceutically acceptable tautomer, salt, solvate, and/or ester thereof, wherein,

R¹, R², and R³ are each independently H, halo, amino, N-alkyl amino, N,N-dialkyl amino, amido, nitro, cyano, hydroxyl, alkoxy, or an optionally substituted C_I-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, nitro, and alkoxy; and

R⁵ is H, an optionally substituted C₁-C₆ alky, C₂-C₆ alkenyl, or C₂-C₁₀ alkynyl;

wherein the substituents are selected from the group consisting of hydroxyl, halo, amino, nitro, and alkoxy.

14. The pharmaceutical composition of claim 10, wherein the typical nicotinic agonist is acetylcholine or nicotine.

15. The pharmaceutical composition of claim 11, wherein the typical nicotinic agonist is acetylcholine or nicotine.

16. The pharmaceutical composition of claim 9, further comprising at least one additional active agent.

17. A method of screening one or more compounds to identify one or more nicotinic desensitizers, comprising:

identifying a compound as a nicotinic desensitizer if said compound

(1) has binding affinity (K_d or K_i) less than about 1,000 nM to a nAChR subtype;

(2) has agonist activity (E_max) to the nAChR subtype less than about 10% of the E_max of a typical nicotinic agonist to the nAChR subtype; and

(3) has potency of inhibiting receptor activation of the nAChR subtype by the typical agonist (IC_50(A)) more than about 1,000 nM when the compound is applied to the nAChR subtype simultaneously with the typical nicotinic agonist.

18. The method of claim 17, further comprising

determining the binding affinity (K_d or K_i) of each of the one or more compounds to a nAChR subtype;

determining the agonist activity (E_max) of each of the one or more compounds to the nAChR subtype; and

determining the antagonist activity of each of the one or more compounds to the nAChR subtype (IC_50(A)) by measuring the activation of channel function of a receptor of the nAChR subtype when each of the one or more compounds is applied to the nAChR subtype simultaneously with a typical nicotinic agonist.

21. The method of claim 17, wherein the typical nicotinic agonist is acetylcholine or nicotine.

19. A method of screening one or more compounds to identify one or more nicotinic desensitizers, comprising:

identifying a compound as a nicotinic desensitizer if said compound

(1) has agonist activity (E_max) to a nAChR subtype less than 10% of the E_max of a typical nicotinic agonist to the nAChR subtype;

(2) has potency of inhibiting receptor activation of the nAChR subtype by the typical nicotinic agonist via desensitization (IC_50(D)) less than about 10,000 nM;

(3) has inhibition of receptor activation of the nAChR subtype by a typical nicotinic agonist (IC_50(A)) more than 1,000 nM when the compound is applied to the nAChR subtype simultaneously with the typical nicotinic agonist; and

(4) the IC_50(D)<

the IC_50(A);

wherein the desensitization comprises contacting each of the one or more compounds with the nAChR subtype for a period of time before a typical nicotinic agonist is applied to the nAChR subtype.

20. The method of claim 19, further comprising

determining the agonist activity (E_max) of said one or more compounds to the nAChR subtype;

determining the desensitization activity of said one or more compounds to the nAChR subtype (IC_50(D) by measuring the activation of channel function of a receptor of the nAChR subtype after the desensitization; and

determining the antagonist activity of said one or more compounds to the nAChR subtype (IC_50(A)) by measuring the activation of channel function of the receptor of the nAChR subtype when each of the one or more compounds is applied to the the nAChR subtype simultaneously with the typical nicotinic agonist.

22. The method of claim 19, wherein the typical nicotinic agonist is acetylcholine or nicotine.

23. The method of claim 19, wherein the period of time is from about 1 second to about 2 hours.

24. A method of testing one or more desensitizers in an animal behavior or disease model comprising:

administering one or more desensitizers to an animal which belongs to one certain animal model; and

evaluating the physiological and behavioral changes in said animal to determine whether the one or more desensitizers have certain in vivo effects.

25-35. -35. (canceled)