Treating neuropathic pain with neuropeptide FF receptor 2 agonists

• US 20050136444A1
• Filed: 09/24/2004
• Published: 06/23/2005
• Est. Priority Date: 09/25/2003
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Kelly, Nicholas Michael, Bertozzi, Fabio, Lameh, Jelveh, Vanover, Kimberly E., Gardell, Luis Roberto, Davis, Robert E., Scully, Audra L.
• Application Number:
  US10/949,140
• Publication Number:
  US 20050136444A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 281/18 the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/2842 Pain, e.g. neuropathic pain, psychogenic pain
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/502 for testing non-proliferative effects
• 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
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: G01N 33/9406 Neurotransmitters

Abstract

The invention described below relates to the discovery of the neuropeptide FF receptor subtype that mediates acute nociception and chronic neuropathic pain, compounds that selectively interact with this receptor subtype and methods for treating acute pain and chronic neuropathic pain.

Claims

1. A method of identifying a compound effective in treating pain comprising contacting said compound with an NPFF2 receptor and determining whether said compound binds to said NPFF2 receptor.

12. The method of claim 1, further comprising the step of identifying an individual in need of pain treatment prior to the contacting step.

2. A method of screening for a compound able to affect one or more activities of an NPFF2 receptor comprising the steps of,

a) contacting a recombinant cell with a test compound, wherein said recombinant cell comprises a recombinant nucleic acid expressing said NPFF2 receptor, provided that said cell does not have functional NPFF2 receptor expression from endogenous nucleic acid, and

b) determining the ability of said test compound to affect one or more activities of said NPFF2 receptor, and comparing said ability with the ability of said test compound to affect said one or more NPFF2 receptor activities in a cell not comprising said recombinant nucleic acid;

wherein said recombinant nucleic acid comprises an NPFF2 receptor nucleic acid selected from the group consisting of;

a) nucleic acid of SEQ ID NO;

1,

b) nucleic acid encoding the amino acid SEQ ID NO;

2,

c) a derivative thereof encoding said NPFF2 receptor, wherein said derivative encodes a receptor having one or more activities of said NPFF2 receptor and comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to a complement of at least 20 contiguous nucleotides of SEQ ID NO;

1.

3. The method of claim 2, wherein said NPFF2 receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO:

2 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO;

2.

4. A method for treating acute and chronic pain of any type comprising contacting an organism with an effective amount of at least one compound wherein the compound activates an NPFF2 receptor subtype.

5. The method of claim 4 wherein the pain is associated with diabetes, viral infection, irritable bowel syndrome, amputation, cancer, or chemical injury.

6. A method of identifying a compound which is an agonist of an NPFF2 receptor, the method comprising:

contacting said NPFF2 receptor with at least one test compound; and

determining any increase in activity level of said NPFF2 receptor so as to identify a test compound which is an agonist of said NPFF2 receptor.

7. The method of claim 6, wherein the identified agonist activates the NPFF2 but not the NPFF1 receptor.

8. The method of claim 6, wherein the identified agonist is selective for the NPFF2 receptor.

10. The method of claim 7, wherein the cells of said culturing step overexpress said NPFF2 receptor.

9. A method of identifying a compound which is an agonist of an NPFF2 receptor, the method comprising:

culturing cells which express the NPFF2 receptor;

incubating the cells or a component extracted from the cells with at least one test compound; and

determining any increase in activity of the NPPF2 receptor so as to identify a test compound which is an agonist of a NPFF receptor.

11. A method for treating pain comprising

contacting an individual suffering from pain with an effective amount of at least one compound of Formula I or II,

whereby one or more symptoms of the pain are reduced;

wherein said compound of Formula I or II has the following structure;

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,

wherein

R₁ is selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, and C₃-C₁₀ cycloalkyl;

each of R₂, R₃, R₄, R₅ and R₆ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, C₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, —

OR₇, —

(NR₇)₂, —

CN, —

C(═

Z)R₇, —

C(═

Z)OR₇, —

C(═

Z)N(R₇)₂, —

(NR₇)—

C(═

Z)R₇, —

(NR₇)—

C(═

Z)N(R₇)₂, —

OC(═

Z)R₇, and —

SR₇

wherein Z is oxygen or sulfur; and

wherein each R₇ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, aryl, and heteroaryl;

or

R₂ and R₃ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₃ and R₄ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₄ and R₅ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₅ and R₆ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring; and

Q is selected from the group consisting of aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring.

13. The method of claim 11, wherein said compound of Formula I or II selectively activates the NPFF2 receptor subtype.

14. The method of claim 11, wherein the pain is associated with diabetes, viral infection, irritable bowel syndrome, amputation, cancer, inflammation or chemical injury.

15. The method of claim 11, wherein the pain is neuropathic pain.

16. The method of claim 15, wherein the subject presents hyperalgesia.

17. The method of claim 15, wherein the subject presents allodynia.

18. A method of identifying a compound that alleviates hyperalgesia or allodynia in a subject, comprising:

providing a subject suffering from hyperalgesia or allodynia with at least one compound of Formula I or II; and

determining if said at least one compound reduces hyperalgesia or allodynia in the subject;

wherein said compound of Formula I or II has the following structure;

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,

wherein

R₁ is selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, and C₃-C₁₀ cycloalkyl;

each of R₂, R₃, R₄, R₅ and R₆ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, C₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, —

OR₇, —

(NR₇)₂, —

CN, —

C(═

Z)R₇, —

C(═

Z)OR₇, —

C(═

Z)N(R₇)₂, —

(NR₇)—

C(═

Z)R₇, —

(NR₇)—

C(═

Z)N(R₇)₂, —

OC(═

Z)R₇, and —

SR₇

wherein Z is oxygen or sulfur; and

wherein each R₇ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, aryl, and heteroaryl;

or

R₂ and R₃ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₃ and R₄ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₄ and R₅ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₅ and R₆ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring; and

Q is selected from the group consisting of aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring.

19. The method of claim 18, further comprising the step of identifying a subject suffering from hyperalgesia or allodynia prior to the providing step.

20. The method of claim 18, wherein said at least one compound is selective for the NPFF2 but not NPFF1 receptor.

21. The method of claim 18, wherein said hyperalgesia is thermal hyperalgesia.

22. The method of claim 18, wherein said allodynia is tactile allodynia.

28. The method of claim 21, wherein the identified compound of Formula I or II is selective for the NPFF2 receptor.

23. A method of identifying a compound of Formula I or II, which is an agonist of the NPFF2 receptor, the method comprising:

contacting a NPFF2 receptor with at least one compound of Formula I or II; and

determining any increase in activity level of the NPFF2 receptor so as to identify a compound of Formula I or II, which is an agonist of the NPFF2 receptor;

wherein said compound of Formula I or II has the following structure;

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,

wherein

R₁ is selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, and C₃-C₁₀ cycloalkyl;

each of R₂, R₃, R₄, R₅ and R₆ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, C₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, —

OR₇, —

(NR₇)₂, —

CN, —

C(═

Z)R₇, —

C(═

Z)OR₇, —

C(═

Z)N(R₇)₂, —

(NR₇)—

C(═

Z)R₇, —

(NR₇)—

C(═

Z)N(R₇)₂, —

OC(═

Z)R₇, and —

SR₇

wherein Z is oxygen or sulfur; and

wherein each R₇ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, aryl, and heteroaryl;

or

R₂ and R₃ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₃ and R₄ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₄ and R₅ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₅ and R₆ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring; and

Q is selected from the group consisting of aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring.

24. A method of identifying a compound which is an agonist of a NPFF2 receptor, the method comprising:

culturing cells that express the NPFF2 receptor;

incubating the cells with at least one compound of Formula I or II; and

determining any increase in activity of the NPPF2 receptor so as to identify a compound of Formula I or II which is an agonist of a NPFF receptor;

wherein said compound of Formula I or II has the following structure;

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,

wherein

R₁ is selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, and C₃-C₁₀ cycloalkyl;

each of R₂, R₃, R₄, R₅ and R₆ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, C₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, —

OR₇, —

(NR₇)₂, —

CN, —

C(═

Z)R₇, —

C(═

Z)OR₇, —

C(═

Z)N(R₇)₂, —

(NR₇)—

C(═

Z)R₇, —

(NR₇)—

C(═

Z)N(R₇)₂, —

OC(═

Z)R₇, and —

SR₇

wherein Z is oxygen or sulfur; and

wherein each R₇ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, aryl, and heteroaryl;

or

R₂ and R₃ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₃ and R₄ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₄ and R₅ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₅ and R₆ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring; and

Q is selected from the group consisting of aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring.

25. The method of claim 24, wherein the identified agonist activates the NPFF2 but not the NPFF1 receptor.

26. The method of claim 24, wherein the identified agonist is selective for the NPFF2 receptor.

27. A method of identifying a compound which is an agonist of a NPFF2 receptor, the method comprising:

contacting the NPFF2 receptor with at least one compound of Formula I or II; and

determining whether said compound of Formula I or II binds to said NPFF2 receptor;

wherein said compound of Formula I or II has the following structure;

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,

wherein

R₁ is selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, and C₃-C₁₀ cycloalkyl;

each of R₂, R₃, R₄, R₅ and R₆ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl, C₂-C₁₀ straight chained or branched alkenyl, C₂-C₁₀ straight chained or branched alkynyl, C₃-C₁₀ cycloalkyl, substituted or unsubstituted aryl or heteroaryl, hydroxy, halogenated ether, nitro, amino, halogen, perhaloalkyl, —

OR₇, —

(NR₇)₂, —

CN, —

C(═

Z)R₇, —

C(═

Z)OR₇, —

C(═

Z)N(R₇)₂, —

(NR₇)—

C(═

Z)R₇, —

(NR₇)—

C(═

Z)N(R₇)₂, —

OC(═

Z)R₇, and —

SR₇

wherein Z is oxygen or sulfur; and

wherein each R₇ is independently selected from the group consisting of hydrogen, C₁-C₁₀ straight chained or branched alkyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkenyl optionally substituted with an aryl or heteroaryl, C₂-C₁₀ straight chained or branched alkynyl optionally substituted with an aryl or heteroaryl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl, aryl, and heteroaryl;

or

R₂ and R₃ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₃ and R₄ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₄ and R₅ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring;

or

R₅ and R₆ and the carbons to which they are attached form a fused aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring; and

Q is selected from the group consisting of aryl, heteroaryl, C₅-C₁₀ carbocyclic or heterocyclic ring.

29. A compound of Formula I or II

30. A compound of Formula III

31. A method of treating neuropathic or inflammatory pain in a subject comprising contacting said subject with an antagonist of the NPFF1 receptor, wherein said antagonist is a compound of Formula I, II, or III.

32. A method of treating neuropathic or inflammatory pain in a subject comprising contacting said subject with a weak partial agonist of the NPFF1 receptor, wherein said weak partial agonist is a compound of Formula I, II, or III.

33. A method of treating neuropathic or inflammatory pain in a subject comprising contacting the subject with a combination of a compound of Formula I, II, or III, which acts as an antagonist or partial agonist to NPFF1 receptor, and another compound of Formula I, II, or III, which acts as a full agonist or a partial agonist to NPFF2 receptor.

34. A method of treating neuropathic or inflammatory pain in a subject comprising contacting the subject with a compound of Formula I, II, or III, where the compound acts as both an NPFF2 agonist and an NPFF1 antagonist.

35. A method of treating neuropathic or inflammatory pain in a subject comprising contacting the subject with a compound of Formula I, II, or III, where the compound acts as both an NPFF2 partial agonist and an NPFF1 antagonist.

36. A method of treating neuropathic or inflammatory pain in a subject comprising contacting the subject with a compound of Formula I, II, or III, where the compound acts as both an NPFF2 partial agonist and an NPFF1 partial agonist.