Methods of modifying feeding behavior using compounds with afinity for the human hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5)

• US 6,645,774 B1
• Filed: 11/23/1999
• Issued: 11/11/2003
• Est. Priority Date: 12/02/1994
• Status: Expired due to Fees

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: Synaptic Pharmaceutical Corporation (Lundbeck Foundation)
• Inventors: Gerald, Christophe P. G., Branchek, Theresa, Weinshank, Richard L., Walker, Mary W.
• Primary Examiner(s): Kemmerer, Elizabeth
• Assistant Examiner(s): WEGERT, SANDRA L
• Application Number:
  US09/447,907
• Time in Patent Office: 1,449 Days
• Field of Search: 435/130.1, 435/320.1, 435/325, 435/69.1, 435/252.3, 435/254.2, 435/348, 435/365, 435/369, 435/7.2, 435/7.21, 536/23.5, 536/23.4, 436/501, 436/503, 514/183, 514/85, 514/107, 530/350
• US Class Current: 436/501
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material

Abstract

This invention provides methods of modifying feeding behavior, including increasing or decreasing food consumption, e.g., in connection with treating obesity, bulimia or anorexia. These methods involve administration of compounds that are selective agonists or antagonists for the Y5 receptor. One such compound has the structure:

In addition, this invention provides an isolated nucleic acid molecule encoding a Y5 receptor, an isolated Y5 receptor protein, vectors comprising an isolated nucleic acid molecule encoding a Y5 receptor, cells comprising such vectors, antibodies directed to the Y5 receptor, nucleic acid probes useful for detecting nucleic acid encoding Y5 receptors, antisense oligonucleotides complementary to any unique sequences of a nucleic acid molecule which encodes a Y5 receptor, and nonhuman transgenic animals which express DNA encoding a normal or a mutant Y5 receptor.

Claims

1. A method of treating a mammalian subject afflicted with obesity which comprises administering to the subject a non-peptidyl compound which is a Y5 receptor antagonist in an amount effective to inhibit the activity of the subject'"'"'s Y5 receptor, wherein the compound binds to the human Y5 receptor (SEQ ID NO:

4) (a) with a K_i less than 50 nanomolar when measured in the presence of ¹²⁵I-PYY at a predetermined concentration, and (b) with an affinity greater than ten-fold higher than the affinity with which the compound binds to each of the human Y1, human Y2 and human Y4 receptors.

2. The method of claim 1, wherein the compound binds to the human Y5 receptor with a K_i less than 10 nanomolar when measured in the presence of ¹²⁵I-PYY at a predetermined concentration.

3. The method of claim 2, wherein the binding of the compound to each of the human Y1, human Y2 and human Y4 receptors is characterized by a K_i greater than 100 nanomolar when measured in the presence of ¹²⁵I-PYY at a predetermined concentration.

4. The method of claim 1, wherein the binding of the compound to the human Y5 receptor is characterized by a K_i less than 5 nanomolar when measured in the presence of ¹²⁵I-PYY at a predetermined concentration.

5. The method of claim 4, wherein the binding of the compound to each of the human Y1, human Y2 and human Y4 receptors is characterized by a K_i greater than 50 nanomolar when measured in the presence of ¹²⁵I-PYY at a predetermined concentration.

6. The method of claim 1, wherein the compound binds to the human Y5 receptor with an affinity greater than 26-fold higher than the affinity with which the compound binds to the human Y1 receptor.

7. The method of claim 1, wherein the compound binds to the human Y5 receptor with an affinity greater than 22-fold higher than the affinity with which the compound binds to the human Y2 receptor.

8. The method of claim 1, wherein the compound binds to the human Y5 receptor with an affinity greater than 34-fold higher than the affinity with which the compound binds to the human Y4 receptor.

9. The method of claim 8, wherein the compound binds to the human Y5 receptor with an affinity greater than 22-fold higher than the affinity with which the compound binds to the human Y2 receptor.

10. The method of claim 9, wherein the compound binds to the human Y5 receptor with an affinity greater than 26-fold higher than the affinity with which the compound binds to the human Y1 receptor.

11. The method of claim 6, wherein the compound binds to the human Y5 receptor with an affinity greater than 100-fold higher than the affinity with which the compound binds to the human Y1 receptor.

12. The method of claim 7, wherein the compound binds to the human Y5 receptor with an affinity greater than 165-fold higher than the affinity with which the compound binds to the human Y2 receptor.

13. The method of claim 8, wherein the compound binds to the human Y5 receptor with an affinity greater than 143-fold higher than the affinity with which the compound binds to the human Y4 receptor.

14. The method of claim 13, wherein the compound binds to tihe human Y5 receptor with an affinity greater than 165-fold higher than the affinity with which the compound binds to the human Y2 receptor.

15. The method of claim 14, wherein the compound binds to the human Y5 receptor with an affinity greater than 100-fold higher than the affinity with which the compound binds to the human Y1 receptor.

16. The method of claim 15, wherein the compound binds to the human Y5 receptor with an affinity greater than 500-fold higher than the affinity with which the compound binds to each of the human Y1, human Y2, and human Y4 receptors.

17. The method of claim 16, wherein the compound binds to the human Y5 receptor with an affinity greater than 1400-fold higher than the affinity with which the compound binds to each of the human Y1, human Y2, and human Y4 receptors.

18. The method of claim 1, wherein the subject is a human or a canine subject.