Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1- (4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl) piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist

Journal of Medicinal Chemistry

Volumn 45, Issue 21, 2002, Pages 4589-4593

  Sebhat, Iyassu K ^a   Martin, William J ^a   Ye, Zhixiong ^a   Barakat, Khaled ^a   Mosley, Ralph T ^a   Johnston, David B R ^a   Bakshi, Raman ^a   Palucki, Brenda ^a   Weinberg, David H ^a   MacNeil, Tanya ^a   Kalyani, Rubana N ^a   Tang, Rui ^a   Stearns, Ralph A ^a   Miller, Randy R ^a   Tamvakopoulos, Constantin ^a   Strack, Alison M ^a   McGowan, Erin ^a   Cashen, Doreen E ^a   Drisko, Jennifer E ^a   Hom, Gary J ^a   Howard, Andrew D ^a   MacIntyre, D Euan ^a   Van der Ploeg, Lex H T ^a   Patchett, Arthur A ^a   Nargund, Ravi P ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(1,2,3,4 TETRAHYDROISOQUINOLINIUM 3 YLCARBONYL) 1 (4 CHLOROBENZYL) 2 [4 CYCLOHEXYL 4 (1H 1,2,4 TRIAZOL 1 YLMETHYL)PIPERIDIN 1 YL] 2 OXOETHYLAMINE; HORMONE RECEPTOR AFFECTING AGENT; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN 4 RECEPTOR AGONIST; SYNTHETIC PEPTIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DISTRIBUTION VOLUME; DOG; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CONFORMATION; DRUG HALF LIFE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; FOOD INTAKE; IC 50; NONHUMAN; PENIS ERECTION; RAT; RECEPTOR AFFINITY; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; CHO CELLS; CRICETINAE; DOGS; EATING; HUMANS; ISOQUINOLINES; MOLECULAR CONFORMATION; PENILE ERECTION; RATS; RECEPTOR, MELANOCORTIN, TYPE 3; RECEPTOR, MELANOCORTIN, TYPE 4; RECEPTORS, CORTICOTROPIN; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDROISOQUINOLINES; TRIAZOLES;

EID: 0037057558     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm025539h     Document Type: Article

References (26)

1. Mountjoy, K. G.; Mortrud, M. T.; Low, M. J.; Simerley, R. B.; Cone, R. D. Localization of the MC-4 Receptor in Neuroendocrine and Autonomic Control Circuits in the Brain. Mol. Endocrinol. 1994, 8, 1298-1308.
2. Vergoni, A. V.; Bertolini, A. Role of Melanocortins in the Central Control of Feeding. Eur. J. Pharmacol. 2000, 405, 25-32.
3. Bultman, S. J.; Michaud, E. J.; Woychik, R. P. Molecular Characterization of the Mouse Agouti Locus. Cell 1992, 71, 1195-1204.
4. Lu, D.; Willard, D.; Patel, I. R.; Kandell, S.; Overton, L.; Kost, T.; Luther, M.; Chen, W.; Woychik, R. P.; Wilkison, W. O.; Cone, R. Agouti Protein is an Antagonist of the Melanocyte Stimulating Hormone Receptor. Nature 1994, 371, 799-802.
5. Kask, A.; Rago, L.; Wikberg, J. E. S.; Schiotch, H. B. Evidence of Involvement of the Melanocortin MC4 Receptor in the Effects of Leptin on Food Intake and Body Weight. Eur. J. Pharmacol. 1998, 360, 15-19.
6. Fan, W.; Boston, B. A.; Kesterson, R. A.; Hruby, V. J.; Cone, R. D. Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome. Nature 1997, 385, 165-168.
7. Murphy, B.; Nunes, C. N.; Ronan, J. J.; Harper, C. M.; Beall, M. J.; Hanaway, M.; Fairhurst, A. M.; Van der Ploeg, L. H. T.; MacIntyre, D. E.; Mellin, T. N. Melanocortin Mediated Inhibition of Feeding Behavior in Rats. Neuropeptides 1998, 32, 491-497.
8. Giraudo, S. Q.; Billington, C. J.; Levine, A. S. Feeding Effects of Hypothalmic Injection of Melanocortin 4 Receptor Ligands. Brain Res. 1998, 809, 302-306.
9. Ollmann, M. M.; Wilson, B. D.; Yang, Y.; Kerns, J. A.; Chen, Y.; Gantz, I.; Barsh, G. S. Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein. Science 1997, 278, 135-138.
10. Kask, A.; Rago, L.; Mutulis, F.; Pahkla, R.; Wikberg, J. E. S.; Schiotch, H. B. Selective Antagonists for the Melanocortin 4 Receptor (HS014) Increases Food Intake in Free-Feeding Rats. Biochem. Biophys. Res. Commun. 1998, 245, 90-93.
11. Huszar, D.; Lynch, C. A.; Fairchild-Huntress; Dunmore, J. H.; Fang, Q.; Berkemeier, L. R.; Gu, W.; Kesterson, R. A.; Boston, B. A.; Cone, R. D.; Smith, F. J,; Campfield, L. A.; Burn, P.; Lee, F. Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice. Cell 1997, 88, 131-141.
12. Bertolini, A.; Gessa, G. L.; Ferrari, W. Penile Erection and Ejaculation: A Central Effect of ACTH-like peptides in Mammals. In Pharmacology and Biochemistry; Sandler, M., Gessa, G. L., Eds.; Raven Press: New York 1975.
13. Al-Obeidi, F.; Hadley, M. E.; Pettitt, B. M.; Rhuby, V. J. Design of a New Class of Superpotent Cyclic α-Melanotropins Based on Quenched Dynamic Simulations. J. Am. Chem. Soc. 1989, 111, 3413-3416.
14. Wessells, H.; Fuciarelli, K.; Hansen, J.; Hadley, M. E.; Hruby, V. J.; Dorr, R.; Levine, N. Synthetic Melanotropic Peptide Initiates Erections in Men with Psychogenic Erectile Dysfunction. J. Urol. 1998, 160, 389-393.
15. Wessells, H.; Gralnek, D.; Dorr, R.; Hruby, V. J.; Hadley, M. E.; Levine, N. Effect of an Alpha-Melanocyte Stimulating Hormone Analog on Penile Erection and Sexual Desire in Men with Organic Erectile Dysfunction. Urologia 2000, 56, 641-646.
16. Bednarek, M. A.; MacNeil, T.; Kalyani, R. N.; Tang, R.; van der Ploeg, L. H. T.; Weinberg, D. H. Selective, High Affinity Peptide Antagonists of α-Melanotropin Action at Human Melanocortin Receptor 4: Their Synthesis and Biological Evaluation in Vitro. J. Med. Chem. 2001, 44, 3665-3672.
17. Al-Obeidi, F.; de L. Castrucci, A. M.; Hadley, M. E.; Rhuby, V. J. Potent and Prolonged Acting Cyclic Lactam Analogues of α-Melanotropin: Design Based on Molecular Dynamics. J. Med. Chem. 1989, 32, 2555-2561.
18. Hruby, V. J.; Lu, D.; Sharma, S. D.; de L. Castrucci, A.; Kesterson, R. A.; Al-Obeidi, F. A.; Hadley, M. E.; Cone, R. D. Cyclic Lactam α-Melanotropin Analogues of Ac-4-Cyclo [Asp5,D-Phe7,Lys 10] α-Melanocyte-Stimulating-(4-10)-NH2 with Bulky Aromatic Amino Acids at Position 7 Show High Antagonist Potency and Selectivity at Specific Melanocortin Receptors. J. Med. Chem. 1995, 38, 3454-3461.
19. Castrucci, A. M.; Sherbrooke, W. C.; Sawyer, T. K.; Staples, D. J.; Tuma, M. C.; Hadley, M. E. Discovery of an alpha-melanotropin antagonist effective in vivo. Peptides 1994, 15, 627-632.
20. Nargund, R. P.; Patchett, A. A.; Bach, M. A.; Murphy, M. G.; Smith, R. Peptidomimetic Growth Hormone Secretagogues. Design Considerations and Therapeutic Potential. J. Med. Chem. 1998, 41, 3103-3127.
21. Bednarek, M. A.; Silve, M. V.; Arison, B.; MacNeil, T.; Kalyani, R. N.; Huang, R. C.; Weinberg, D. H. Structure-Function Studies on the Cyclic Peptide MT-II, Derivative of α-Melanotropin. Peptides 1999, 20, 401-409.
22. Miller, M. D.; Sheridan, R. P.; Kearsley, S. K. SQ - a program for rapidly producing pharmacophorically relevant molecular superpositions. J. Med. Chem. 1999, 42, 1505-1514.
23. Strack, A. M.; et al. Unpublished results.
24. Sachs, B. D. Contextual approaches to the physiology and classification of erectile function, erectile dysfunction, and sexual arousal. Neurosci. Biobehav. Rev. 2000, 24, 541-560.
25. Martin, W. J.; et al. Activation of MC4R Increases Erectile Activity in Rats Ex Copula. Eur. J. Pharmacol., in press.
26. van der Ploeg, L. H. T.; Martin, W. J.; Howard, A. D.; Nargund, R. P.; Austin, C. P.; Guan, X.; Drisko, J.; Cashen, D.; Sebhat, I.; Patchett, A. A.; Figueroa, D. J.; DiLella, A. G.; Connolly, B. M.; Weinberg, D. H.; Tan, C. T.; Palyha, O. C.; Pong, S.; MacNeil, T.; Rosenblum, C.; Vongs, A.; Tang, R.; Yu, H.; Sailer, A. W.; Fong, T. M.; Huang, C.; Tota, M.; Chang, R. S.; Stearns, R.; Tamvakopoulos, C.; Christ, G.; Drazen, D. L.; Spar, B. D.; Nelson, R. J.; MacIntyre, D. E. A role for the melanocortin 4 receptor in sexual function. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 11381.