THYROTROPIN RELEASING HORMONE RECEPTOR-OREXIN RECEPTOR HETERO-DIMERS/-OLIGOMERS

• US 20100234417A1
• Filed: 11/09/2007
• Published: 09/16/2010
• Est. Priority Date: 11/10/2006
• Status: Abandoned Application

• Current Assignee: Dimerix Bioscience Pty Ltd. (Dimerix Ltd.)
• Original Assignee: Dimerix Bioscience Pty Ltd. (Dimerix Ltd.)
• Inventors: Eidne, Karin Ann, Boon, Heng See, Seeber, Ruth Marie, Pfleger, Kevin Donald George
• Application Number:
  US12/514,034
• Publication Number:
  US 20100234417A1
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: G01N 33/542 with steric inhibition or signal modification, e.g. fluorescent quenching

Abstract

A hetero-dimeric or hetero-oligomeric receptor, comprising at least one thyrotropin releasing hormone receptor subunit associated with at least one orexin receptor subunit.

Claims

1. A hetero-dimeric or hetero-oligomeric receptor, comprising at least one thyrotropin releasing hormone receptor subunit associated with at least one orexin receptor subunit.

2. A method for the treatment of a patient suffering from an orexin-related ailment by administering a therapeutically effective amount of a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

3. A method according to claim 2, wherein the thyrotropin-releasing hormone receptor agonist, inverse agonist or antagonist is co-administered with an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

4. A method for the treatment of a patient suffering from a thyrotropin-releasing hormone-related ailment by administering a therapeutically effective amount of an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

5. A method according to claim 4, wherein the orexin receptor agonist, inverse agonist or antagonist is co-administered with a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

6. A method for the manufacture of a medicament for the treatment of a patient suffering from an orexin-related ailment, said medicament comprising a therapeutically effective amount of a thyrotropin releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

7. The method according to claim 6, wherein the medicament further comprises an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

8. A method for the manufacture of a medicament for the treatment of a patient suffering from a thyrotropin-releasing hormone-related ailment, said medicament comprising a therapeutically effective amount of an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

9. The A method according to claim 8, wherein the medicament further comprises a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

10. A method for the manufacture of a medicament for the treatment of a patient suffering from an orexin-related ailment said medicament comprising a therapeutically effective amount of a thyrotropin-releasing hormone-selective binding agent, or fragment thereof.

11. The method according to claim 10, wherein the thyrotropin-releasing hormone-selective binding agent is an antibody, a humanised antibody, a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody or an anti-idiotypic antibody.

12. A method for the manufacture of a medicament for the treatment of a patient suffering from a thyrotropin-releasing hormone-related ailment, said medicament comprising a therapeutically effective amount of an orexin-selective binding agent, or fragment thereof.

13. The method according to claim 12, wherein the orexin-selective binding agent is an antibody, a humanised antibody, a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody or an anti-idiotypic antibody.

14. A method for screening a test compound for thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer selective activity, the method comprising the steps of:

a) determining whether, and/or the extent to which, the test compound interacts with the orexin receptor while the orexin receptor is associated with the thyrotropin releasing hormone receptor; and

b) if the test compound interacts with the orexin receptor while the orexin receptor is associated with the thyrotropin releasing hormone receptor, determining whether, or the extent to which the test compound interacts with the orexin receptor in the absence of the thyrotropin releasing hormone receptor;

such that the test compound that exhibits greater affinity and/or potency and/or efficacy when interacting with the orexin receptor while the orexin receptor is associated with the thyrotropin releasing hormone receptor is selective for the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

15. A method for screening a test compound for thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer selective activity, the method comprising the steps of:

a) determining whether, and/or the extent to which, the test compound interacts with the thyrotropin releasing hormone receptor while the thyrotropin releasing hormone receptor is associated with the orexin receptor; and

b) if the test compound interacts with the thyrotropin releasing hormone receptor while the thyrotropin releasing hormone receptor is associated with the orexin receptor, determining whether, or the extent to which the test compound interacts with the thyrotropin releasing hormone receptor in the absence of the orexin receptor;

such that the test compound that exhibits greater affinity and/or potency and/or efficacy when interacting with the thyrotropin releasing hormone receptor while the thyrotropin releasing hormone receptor is associated with the orexin receptor is selective for the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

16. A method for screening a test compound for thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer selective antagonism or partial agonism, the method comprising the steps of:

determining whether, and/or the extent to which, the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, by contacting said test compound with a system comprising;

i) a first agent, comprising the orexin receptor coupled to a first reporter component;

ii) a second agent, comprising an interacting group coupled to a second reporter component;

iii) a third agent, comprising the thyrotropin releasing hormone receptor;

iv) an agonist of the orexin receptor, the thyrotropin releasing hormone receptor and/or the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer;

wherein proximity of the first and second reporter components generates a signal; and

wherein the modulator modulates the association of the interacting group with the thyrotropin releasing hormone receptor;

b) detecting a decrease in the signal as a determination of whether and/or the extent to which the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer; and

c) if the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, determining whether, or the extent to which the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor in the absence of the orexin receptor and the orexin receptor in the absence of the thyrotropin releasing hormone receptor;

such that a test compound that exhibits greater antagonistic or partial agonistic properties when interacting with the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer is selective for the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

17. A method for screening a test compound for thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer selective antagonism or partial agonism, the method comprising the steps of:

a) determining whether, and/or the extent to which, the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, by contacting said test compound with a system comprising;

i) a first agent, comprising the thyrotropin releasing hormone receptor coupled to a first reporter component;

ii) a second agent, comprising an interacting group coupled to a second reporter component;

iii) a third agent, comprising the orexin receptor; and

iv) an agonist of the orexin receptor, the thyrotropin releasing hormone receptor and/or the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer;

wherein proximity of the first and second reporter components generates a signal; and

wherein the modulator modulates the association of the interacting group with the orexin receptor;

b) detecting a decrease in the signal as a determination of whether and/or the extent to which the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer; and

c) if the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, determining whether, or the extent to which the test compound is an antagonist or partial agonist of the thyrotropin releasing hormone receptor in the absence of the orexin receptor and the orexin receptor in the absence of the thyrotropin releasing hormone receptor;

such that a test compound that exhibits greater antagonistic or partial agonistic properties when interacting with the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer is selective for the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

18. A method for screening a test compound for thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer selective inverse agonism, the method comprising the steps of:

a) determining whether, and/or the extent to which, the test compound is an inverse agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, by contacting said test compound with a system comprising;

i) a first agent, comprising the orexin receptor coupled to a first reporter component;

ii) a second agent, comprising an interacting group coupled to a second reporter component; and

iii) a third agent, comprising a constitutively active thyrotropin releasing hormone receptor;

wherein proximity of the first and second reporter components generates a signal; and

wherein the modulator modulates the association of the interacting group with the thyrotropin releasing hormone receptor;

b) detecting a decrease in the signal as a determination of whether and/or the extent to which the test compound is an inverse agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer; and

c) if the test compound is an inverse agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, determining whether, or the extent to which the test compound is an inverse agonist of the thyrotropin releasing hormone receptor in the absence of the orexin receptor and the orexin receptor in the absence of the thyrotropin releasing hormone receptor;

such that a test compound that exhibits greater inverse agonistic properties when interacting with the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer is selective for the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

19. A method for screening a test compound for thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer inverse agonism, the method comprising the steps of:

a) determining whether, and/or the extent to which, the test compound is an inverse agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, by contacting said test compound with a system comprising;

i) a first agent, comprising the thyrotropin-releasing hormone receptor coupled to a first reporter component;

ii) a second agent, comprising an interacting group coupled to a second reporter component;

iii) a third agent, comprising a constitutively active orexin receptor; and

wherein proximity of the first and second reporter components generates a signal; and

wherein the modulator modulates the association of the interacting group with the orexin receptor;

b) detecting a decrease in the signal as a determination of whether and/or the extent to which the test compound is an inverse agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer; and

c) if the test compound is an inverse agonist of the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer, determining whether, or the extent to which the test compound is an inverse agonist of the thyrotropin releasing hormone receptor in the absence of the orexin receptor and the orexin receptor in the absence of the thyrotropin releasing hormone receptor;

such that a test compound that exhibits greater inverse agonistic properties when interacting with the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer is selective for the thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

20. Selective agonists and/or antagonists and/or inverse agonists and/or partial agonists of the a thyrotropin releasing hormone receptor/orexin receptor hetero-dimer/-oligomer.

21. A method for the treatment of a patient suffering from a thyrotropin-releasing hormone-related ailment by administering a therapeutically effective amount of a selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist.

22. A method according to claim 21, wherein the selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist is co-administered with a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

23. A method according to claim 21, wherein the selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist is co-administered with an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

24. A method for the treatment of a patient suffering from a orexin-related ailment by administering a therapeutically effective amount of a selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist.

25. A method according to claim 24, wherein the selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist is co-administered with a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

26. A method according to claim 24, wherein the selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist is co-administered with an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

27. A method for the manufacture of a medicament for the treatment of a patient suffering from a thyrotropin-releasing hormone-related ailment comprising use of a therapeutically effective amount of a selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist.

28. A method according to claim 27, wherein the medicament contains an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

29. A method according to claim 27, wherein medicament contains a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.

30. A method for the manufacture of a medicament for the treatment of a patient suffering from an orexin-related ailment comprising use of a therapeutically effective amount of a selective orexin receptor/thyrotropin-releasing hormone receptor hetero-dimer/-oligomer agonist, inverse agonist, partial agonist or antagonist.

31. A method according to claim 30, wherein the medicament contains an orexin receptor agonist, inverse agonist, partial agonist or antagonist.

32. A method according to claim 30, wherein the medicament contains a thyrotropin-releasing hormone receptor agonist, inverse agonist, partial agonist or antagonist.