Approaches to the rational design of selective melanocortin receptor antagonists

Expert Opinion on Drug Discovery

Volumn 6, Issue 5, 2011, Pages 543-557

  Hruby, Victor J ^a   Cai, Minying ^a   Nyberg, Joel ^a   Muthu, Dhanasekaran ^a  

^a University of Arizona   (United States)

Author keywords

allosteric antagonist; melanocortin receptors; orthosteric antagonists; receptor antagonists

Indexed keywords

HORMONE RECEPTOR BLOCKING AGENT; LIGAND; MELANOCORTIN 1 RECEPTOR; MELANOCORTIN 1 RECEPTOR ANTAGONIST; MELANOCORTIN 2 RECEPTOR; MELANOCORTIN 2 RECEPTOR ANTAGONIST; MELANOCORTIN 3 RECEPTOR; MELANOCORTIN 3 RECEPTOR ANTAGONIST; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN 4 RECEPTOR ANTAGONIST; MELANOCORTIN 5 RECEPTOR; MELANOCORTIN 5 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ADRENAL CORTEX; ALLOSTERISM; DRUG DESIGN; DRUG STRUCTURE; FEEDING BEHAVIOR; HUMAN; IC 50; MUTAGENESIS; NONHUMAN; PRIORITY JOURNAL; REVIEW;

EID: 79955404363     PISSN: 17460441     EISSN: None     Source Type: Journal    
DOI: 10.1517/17460441.2011.565743     Document Type: Review

References (81)

1. Hadley ME, editor, The Melanotropic peptides, Volumes I, II and III, CRC Press, Boca Raton, FL, 1988
2. Cone RD, editor, The melanocortin system. Ann NY Acad Sci 2003;994:387
3. Cone RD, editor, The melanocortin receptors. Humana Press, Inc.: Totowa NJ; 2000. p. 551
4. Vandry H, Eberle AN, editors, The melanotropic peptides. Ann NY Acad Sci 1993;680:687
5. Kreiger DT, Ganong WF, editors, ACTH and related peptides: structure, regulation and action. Ann NY Acad Sci 1977;297:664
6. Sawyer TK, Sanfilippo PJ, Hruby VJ, et al. [Nle4, D-Phe7]-alpha- melanocyte stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci USA 1980;77:5754-8 (Pubitemid 11206397)
7. Al-Obeidi F, Hadley ME, Pettitt BM, et al. Design of a new class of superpotent cyclic alpha-melanotropins based on quenched dynamic simulations. J Amer Chem Soc 1989;111:3413-16 (Pubitemid 19118541)
8. Al-Obeidi F, de Lauro Castrucci AM, Hadley ME, et al. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J Med Chem 1989;32:2555-61 (Pubitemid 20002805)
9. Hruby VJ, Lu D, Sharma SD, et al. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-c[Asp5,D-Phe7, Lys10]alpha-MSH(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;38:3454-61
10. Al-Obeidi F, Hruby VJ, Hadley ME, et al. Design, synthesis and biological activities of a potent and selective alpha-melanotropin antagonist. Int J Peptide Protein Res 1990;35:228-34 (Pubitemid 20126878)
11. Medzihradszky K, The bio-organic chemistry of alpha-melanotropin. Medical Res Rev 1982;2:247-70
12. Seelig S, Lindley BD, Sayers G. A new approach to the structure-activity relationship for ACTH analogs using isolated adrenal cortex cells. Methods Enzymol 1975;39D:347-59
13. Schwyzer R. ACTH: a short introduction review. In: Kreiger DT, Ganong WF, editors, ACTH and related peptides: structure, regulation and action. Ann NY Acad Sci 1977;297:3-26
14. Hruby VJ. Conformational restrictions of biologically active peptides via amino acid side chain groups. Life Sci 1982;31:189-99 (Pubitemid 12026247)
15. Hruby VJ. Design of peptide superagonists and antagonists: conformational and dynamic considerations. In: Vida JA, Gordon M, editors, Conformationally directed drug design peptides and nucleic acids as templates or targets. ACS Symposium Series No. 251, Washington, DC; 1984. p. 9-27
16. Hruby VJ, Al-Obeidi F, Kazmierski WM. Emerging approaches in the molecular design of receptor selective peptide ligands: conformational, topographical and dynamic considerations. Biochemical J 1990;268:249-62 (Pubitemid 20193959)
17. Cowell SM, Balse-Srinivasan PM, Ahn JM, et al. Design and synthesis of peptide antagonists and inverse agonists for G-protein coupled receptors. Volume Iyengar R Hildebrandt JD editors Methods in Enzymology. Academic Press, San Diego, CA; 2002. p. 49-72.
18. Hruby VJ. Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov 2002;1:847-58 (Pubitemid 37361580)
19. Hruby VJ, Wilkes BC, Cody WL, et al. Melanotropins: structural, conformational, and biological considerations in the development of superpotent and superprolonged analogs. Peptide Protein Rev 1984;3:1-64
20. Hruby VJ, Li G, Haskell-Luevano C, et al. Design of peptides, proteins, and peptidomimetics in chi space. Biopolymers 1997;43:219-66
21. Doedens L, Opperer F, Cai M, et al. Multiple N-Methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies. J Amer Chem Soc 2010;132:8115-28
22. Golz S, Bruggermeier U, Geerts A. Diagnostics, drug screening and therapeutics for diseases associated with human melanocortin 1 receptor ( MC1R ). US20070037226; 2007
23. Xia Y, Wikberg J, Chhajlani V. Expression of melanocortin 1 receptors in periaqueductal gray matter. Neuroreport 1995;6:2193-6
24. Mogil JS, Wilson SG, Chesler EJ, et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 2003;100:4867-72 (Pubitemid 36457820)
25. Liem E, Joinen T, Tsueda K, et al. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology 2005;102:509-14 (Pubitemid 40315138)
26. Han G, Quillan JM, Carlson K, et al. Design of novel chimeric melanotropin-deltorphin analogues. Discovery of the first potent human melanocortin 1 receptor antagonist. J Med Chem 2003;46:810-19 (Pubitemid 36258871)
27. Mayorov AV, Han SY, Cai M, et al. Effects of macrocycle size and rigidity on melanocortin receptor-1 and -5 selectivity in cyclic lactam alpha-melanocyte-stimulating hormone analogs. Chem Biol Drug Design 2006;67:329-35
28. Juni A, Cai M, Stankova M, et al. Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor. Anesthesiology 2010;112:181-8
29. Kapas S, Cammas F, Hinson J, et al. Agonist and receptor binding properties of adrenocorticotropin peptides using the cloned mouse adrenocorticotropin receptor expressed in a stably transfected HeLa cell line. Endocrinology 1996;137:3291-4 (Pubitemid 26250177)
30. Hofmann K, Montibeller JA, Finn FM. ACTH antagonists. Proc Natl Acad Sci USA 1974;71:80-3
31. Kovalitskaya IA, Kolobov AA, Kampe-Nemm EA, et al. Synthetic peptide KKRR corresponding to the human ACTH fragment 15-18 is an antagonist of the ACTH receptor. Russ J Bioorg Chem 2008;34:24-9 (Pubitemid 351650937)
32. Navolotskaya EV, Kovalitskaya YA, Sadovnikov VB, et al. Synthetic ACTH-Like peptide GKVLKKRR, corresponding to the fragment 81-88 of human pro-interleukin-1 alpha, acts as an antagonist of ACTH receptor. Int J Pept Res Ther 2008;14:10-15 (Pubitemid 351321662)
33. Butler AA, Kesterson RA, Khong K, et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000;141(9):3518-21 (Pubitemid 32269044)
34. Ellacott KLJ, Murphy JG, Marks DL, et al. Obesity-induced inflammation in white adipose tissue is attenuated by loss of melanocortin-3 receptor signaling. Endocrinology 2007;148(12):6186-94 (Pubitemid 350146148)
35. Sutton GM, Perez-Tilve D, Nogueiras R, et al. The melanocortin-3 receptor is required for entrainment to meal intake. J Neurosci 2008;28(48):12946-55
36. Getting SJ, Di Filippo C, Christian HC. MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct. J Leukoc Biol 2004;76:1-9
37. Santoro N, Perrone L, Cirillo G, et al. Effect of the melanocortin-3 receptor C17A and G241A variants on weight loss in childhood obesity. Am J Clin Nutr 2007;85(4):950-3 (Pubitemid 46557907)
38. Marks DL, Hruby VJ, Brookhart G, et al. The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R). Peptides 2006;27:259-64 (Pubitemid 43162897)
39. Ni X-P, Butler AA, Cone RD, et al. Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones J Hypertens 2006;24(11):2239-46 (Pubitemid 44611033)
40. Li SJ, Varga K, Archer P, et al. Melanocortin antagonists define two distinct pathways of cardiovascular control by alpha- and gamma-melanocyte- stimulating hormones. J Neurosci 1996;16:5182-8 (Pubitemid 26269676)
41. King SH, Mayorov AV, Balse-Srinivasan P, et al. Melanocortin receptors, melanotroic peptides and penile erection. Curr Topics Med Chem 2007;7:1111-19 (Pubitemid 47044741)
42. Kavarana MJ, Trivedi D, Cai M, et al. Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors. J Med Chem 2002;45:2644-50 (Pubitemid 34600969)
43. Mayorov AV, Cai M, Palmer ES, et al. Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor. J Med Chem 2008;51:187-95
44. Ballet S, Mayorov AV, Cai M, et al. Novel selective human melanocortin- 3 receptor ligands: use of the 4-amino- 1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold. Bioorg Med Chem Lett 2007;17:2492-8 (Pubitemid 46507783)
45. Mayorov AV, Cai M, Chandler KB, et al. Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. J Med Chem 2006;49:1946-52
46. Grieco P, Cai M, Han G, et al. Further structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4 and 5. Peptides 2007;28:1191-6 (Pubitemid 46843380)
47. Grieco P, Lavecchia A, Cai M, et al. Structure-activity studies of the melanocortin peptides: discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors. J Med Chem 2002;45:5287-94 (Pubitemid 35429167)
48. Cai M, Mayorov AV, Cabello C, et al. Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues. J Med Chem 2005;48:1839-48 (Pubitemid 40403064)
49. Chen M, Cai M, Aprahamian CJ, et al. Contribution of the conserved amino acids of the melanocortin-4 receptor in Nle4,DPhe7]- alpha-melanocyte- stimulating hormone binding and signaling. J Biol Chem 2007;282:21712-19 (Pubitemid 47195764)
50. Mountjoy K, Mortrud M, Low M, et al. Localization of the melanocortin-4 receptor (MC4R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994;8:1298-308 (Pubitemid 24335073)
51. Starowicz K, Bilecki W, Sieja A, et al. Melanocortin 4 receptor is expressed in the dorsal root ganglions and down-regulated in neuropathic rats. Neurosci Lett 2004;358:79-82 (Pubitemid 38340725)
52. Tanabe K, Gamo K, Aoki S, et al. Melanocortin receptor 4 is induced in nerve-injured motor and sensory neurons of mouse. J Neurochem 2007;101:1145-52 (Pubitemid 46683870)
53. Fan W, Boston BA, Kesterson RA, et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997;385:165-8 (Pubitemid 27034218)
54. Cone RD. Studies of the physiological functions of the melanocortin system. Endocr Rev 2006;27:736-49 (Pubitemid 44936057)
55. Jean-Christophe P, Hofbauer K. Monoclonal antibodies directed to the melanocortin-4 receptor ( MC4R ) and their use in the treatment of cachexia and related conditions. Can Pat Appl 2009
56. Wessells H, Fuciarelli K, Hansen J, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol 1998;160:389-93 (Pubitemid 29476684)
57. Wessells H, Gralnek D, Dorr R, et al. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology 2000;56:641-6
58. Bednarek MA, MacNeil T, Kalyani RN, et al. Selective, high affinity peptide antagonists of alpha-melanotropin action at human melanocortin receptor 4: their synthesis and biological evaluation in vitro. J Med Chem 2001;44:3665-72 (Pubitemid 33026674)
59. Kask A, Mutulis F, Muceniece R, et al. Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist ( HS024 ): evaluation in vitro and in vivo. Endocrinology 1998;139:5006-14 (Pubitemid 28533449)
60. Balse-Srinivasan P, Grieco P, Cai M, et al. Structure-activity relationships of gamma-melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues. J Med Chem 2003;46(23):4965-73 (Pubitemid 37352035)
61. Schioth HB, Mutulis F, Muceniece R, et al. Discovery of novel melanocortin4 receptor selective MSH analogues. Br J Pharmacol 1998;124:75-82 (Pubitemid 28210046)
62. Skuladottir GV, Jonsson L, Skarhedinsson JO, et al. Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist. Br J Pharmacol 1999;126:27-34 (Pubitemid 29041740)
63. Grieco P, Lavecchia A, Cai M, et al. Structure-activity studies of the melanocortin peptides: discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors. J Med Chem 2002;45(24):5287-94 (Pubitemid 35429167)
64. Chakia S, Ogawab S, Todaa Y, et al. Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents. Eur J Pharmacol 2003;474:95-101
65. Ying J, Gu X, Cai M, et al. Design, synthesis, and biological evaluation of new cyclic melanotropin peptide analogues selective for the human melanocortin-4 receptor J Med Chem 2006;49(23):6888-96 (Pubitemid 44749754)
66. Chaki S, Hirota S, Funakoshi T, et al. Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2- (4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2- methoxynaphthalen-1-yl)butyl] piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor. J Pharmacol Exp Therap 2003;304 (2):818-26 (Pubitemid 36152361)
67. Chaki S, Oshida Y, Ogawa S, et al. MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolyticand antidepressant-like activity. Pharmacol Biochem Behav 2005;82(4):621-6 (Pubitemid 43184037)
68. Jiang W, Tran JA, Tucci FC, et al. Synthesis and characterization of pyrrolidine derivatives as potent agonists of the human melanocortin-4 receptor. Bioorg Med Chem Lett 2007;17(23):6546-52 (Pubitemid 350026326)
69. Sharma S, Shi Y-Q, Wu Z, et al. Bicyclic melanocortin-specific compounds. US 2004/0152134A1; 2004
70. Pontillo J, Arellano M, Tran IA, et al. Structure-activity relationship of a series of cyclohexylpiperidines bearing an amide side chain as antagonists of the human melanocortin-4 receptor. Bioorg Med Chem Lett 2005;15:3434-8 (Pubitemid 40835751)
71. Vos TJ, Balani S, Blackburn V, et al. Identification and structure-activity relationships of a new series of melanocortin-4 receptor antagonists. Bioorg Med Chem Lett 2006;16:2302-5 (Pubitemid 43351098)
72. Nakazato A, Ishii T, Nozawa H. Use of piperazine derivatives as MC4 receptor antagonists and therapeutic agents containing them for treatment anxiety neurosis or depression. JP2005035983; 2005
73. Pontillo J, Tran JA, Markison S, et al. A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice. Bioorg Med Chem Lett 2005;15:2541-6 (Pubitemid 40614986)
74. Yang Y, Cai M, Chen M, et al. Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling. Regul Peptides 2009;155(1-3):46-54
75. Labbe O, Desarnaud F, Eggerickx D, et al. Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry 1994;33(15):4543-9 (Pubitemid 24145102)
76. Chen W, Kelly MA, Opitz-Araya X, et al. Exocrine gland dysfunction in MC5 -R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 1997;91(6):789-98 (Pubitemid 28007735)
77. Hiramoto K, Hashimoto M, Orita K, et al. alpha-Melanocyte-Stimulating hormone plays an important role in the onset of pollinosis in a pollen allergy mouse model. Int Arch Allergy Immunol 2010;153(1):13-18
78. Blaskovich MAT, Cassidy PJ. Preparation of 1,4-diazepan-2-one peptidomimetics as MC5R melanocortin receptor modulators for treating conditions related to this receptor. U.S. Patent Appl Publ Chemical Indexing Equivalent to 151:313916 US. PCT Int Appl 2009:282
79. Balse-Srinivasan PM, Grieco P, Cai M, et al. Structure-activity relationships of novel cyclic alpha-MSH/beta-MSH hybrid analogues that lead to potent and selective ligands for the human MC3R and human MC5R. J Med Chem 2003;46:3728-33 (Pubitemid 36992207)
80. Grieco P, Cai M, Liu L, et al. Design and microwave assisted synthesis of novel macrocyclic peptides active at melanocortin receptors: discovery of potent and selective hMC5R receptor antagonists. J Med Chem 2008;51(9):2701-7 (Pubitemid 351620792)
81. Cain JP, Mayorov AV, Cai M, et al. Design, synthesis, and biological evaluation of a new class of small molecule peptide mimetics targeting the melanocortin receptors. Bioorg Med Chem Lett 2006;16(20):5462-7 (Pubitemid 44332193)