Screening Method

• US 20090069228A1
• Filed: 03/17/2006
• Published: 03/12/2009
• Est. Priority Date: 03/18/2005
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Maruyama, Minoru, Komatsu, Hidetoshi, Itoh, Yasuaki, Mori, Masaaki
• Granted Patent: US 7,919,260 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 25/28 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/2814 Dementia; Cognitive disorders
• 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 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/5041 involving analysis of members of signalling pathways
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92

Abstract

The present invention provides compounds or their salts that promote or inhibit the activities of a protein comprising the same or substantially the same as the amino acid sequence represented by SEQ ID NO: 1, compounds or their salts that promote or inhibit the activities of a gene for said protein, antisense polynucleotides comprising the whole or part of a base sequence complimentary or substantially complimentary to the base sequence of a polynucleotide encoding said protein or its partial peptide, antibodies to said protein, etc. These compounds or their salts, antisense nucleotides, antibodies, etc. can be used as agents for the prevention/treatment of mental disorders, prolactin-related disorders, etc.

Claims

1. A method of screening a compound or a salt thereof that changes the binding property of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1 or a salt thereof, to a ligand capable of specifically binding to said protein or a salt thereof, which comprises using (a) said protein, its partial peptide, or a salt thereof, and (b) said ligand.

2. The screening method according to claim 1, wherein the ligand is a reserpine compound.

3. The screening method according to claim 2, wherein the reserpine compound is a compound represented by the formula:

4. The screening method according to claim 2, wherein the reserpine compound is reserpine.

5. The screening method according to claim 1, wherein the ligand is an indole alkaloid.

6. The screening method according to claim 1, wherein the ligand is a methoctramine compound.

7. The screening method according to claim 6, wherein the methoctramine compound is a compound represented by the formula:

8. The screening method according to claim 6, wherein the methoctramine compound is methoctramine.

9. The screening method according to claim 1, wherein substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1 is the amino acid sequence represented by SEQ ID NO;

3 or SEQ ID NO;

5.

10. The screening method according to claim 1, which comprises assaying the binding amounts of a ligand capable of specifically binding to a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof, to said protein, its partial peptide, or a salt thereof, (a) in the case of contacting said ligand with said protein, its partial peptide, or a salt thereof and (b) in the case of contacting said ligand and a test compound with said protein, its partial peptide, or a salt thereof, and comparing the binding amounts.

11. The screening method according to claim 1, which comprises assaying the binding amounts of a ligand capable of specifically binding to a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof, to a cell containing said protein, its partial peptide, or a salt thereof, or a membrane fraction of the cell, (a) in the case of contacting said ligand with said cell or a membrane fraction of the cell and (b) in the case of contacting said ligand and a test compound with said cell or said membrane fraction, and comparing the binding amounts.

12. The screening method according to claim 10, wherein the protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof is a protein, its partial peptide, or a salt thereof, which protein is expressed on a cell membrane by culturing a transformant containing a DNA encoding said protein, its partial peptide, or a salt thereof.

13. The screening method according to claims 10 to 12, wherein the ligand is a labeled ligand.

14. The screening method according to claim 1, which comprises assaying cell stimulating activities mediated by a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof, (a) in the case of contacting a ligand capable of specifically binding to said protein, its partial peptide, or a salt thereof with said protein, its partial peptide, or a salt thereof and (b) in the case of contacting said ligand and a test compound with said protein, its partial peptide, or a salt thereof, and comparing the cell stimulating activities.

15. The screening method according to claim 1, which comprises assaying cell stimulating activities mediated by a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof, (a) in the case of contacting a ligand capable of specifically binding to said protein, its partial peptide, or a salt thereof with a cell containing said protein, its partial peptide, or a salt thereof or a membrane fraction of said cell and (b) in the case of contacting said ligand and a test compound with a cell containing said protein, its partial peptide, or a salt thereof, or a membrane fraction of said cell, and comparing the cell stimulating activities.

16. The screening method according to claim 15, wherein the cell stimulating activity is a Gs activity.

17. The screening method according to claim 15, wherein the protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof is a protein, its partial peptide, or a salt thereof, which protein is expressed on a cell membrane by culturing a transformant containing a DNA encoding said protein, its partial peptide, or a salt thereof.

18. A method of screening an agonist for a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, or a salt thereof, which comprises (i) assaying cell stimulating activities mediated by said protein, its partial peptide, or a salt thereof, (a) in the case of contacting a ligand capable of specifically binding to said protein, its partial peptide, or a salt thereof with a cell containing said protein, its partial peptide, or a salt thereof, and (b) in the case of contacting a test compound with a cell containing said protein, its partial peptide, or a salt thereof, and comparing the cell stimulating activities, or (ii) assaying cell stimulating activities mediated by said protein, its partial peptide, or a salt thereof, in the case of contacting a test compound with a cell containing said protein, its partial peptide, or a salt thereof.

19. A method of screening an antagonist to a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, or a salt thereof, which comprises assaying cell stimulating activities mediated by said protein, its partial peptide, or a salt thereof, in the case of contacting a test compound with a cell containing said protein, its partial peptide, or a salt thereof, in the presence of a ligand capable of specifically binding to said protein, its partial peptide, or a salt thereof.

20. A kit for screening a compound or a salt thereof that changes the binding properties of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, or a salt thereof to a ligand capable of specifically binding to said protein or a salt thereof, which comprises (a) said protein or a salt thereof and (b) said ligand.

21. An agent for preventing/treating schizophrenia or cognitive impairment, which comprises a compound or a salt thereof that promotes the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

22. An agent for preventing/treating prolactin hyposecretion, which comprises a compound or a salt thereof that promotes the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

23. An agent for preventing/treating Parkinson'"'"'s disease, which comprises a compound or a salt thereof that inhibits the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

24. An agent for preventing/treating hyperprolactinemia, which comprises a compound or a salt thereof that inhibits the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

25. (canceled)

26. A method for preventing/treating schizophrenia or cognitive impairment, which comprises promoting the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

27. A method for preventing/treating prolactin hyposecretion, which comprises promoting the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

28. A method for preventing/treating Parkinson'"'"'s disease, which comprises inhibiting the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

29. A method for preventing/treating hyperprolactinemia, which comprises inhibiting the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

30. A method for preventing/treating schizophrenia or cognitive impairment, which comprises administering to a mammal an effective dose of a compound or a salt thereof that promotes the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

31. A method for preventing/treating prolactin hyposecretion, which comprises administering to a mammal an effective dose of a compound or a salt thereof that promotes the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

32. A method for preventing/treating Parkinson'"'"'s disease, which comprises administering to a mammal an effective dose of a compound or a salt thereof that inhibits the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

33. A method for preventing/treating hyperprolactinemia, which comprises administering to a mammal an effective dose of a compound or a salt thereof that inhibits the activity of a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO:

1, its partial peptide, or a salt thereof.

34-37. -37. (canceled)