Melanotropins as drugs for the treatment of obesity and other feeding disorders: potential and problems.
Current biological and pharmacological evidence suggests that the melanocortin 4 and melanocortin 3 receptors which are seven transmembrane G-protein coupled receptors (GPCRs) are involved in various aspects of energy balance and feeding behaviors in animals including humans. The natural endogenous ligands for these receptors are products of the gene pro-opiomelanocortin (POMC), and include alpha-melanocyte stimulating hormone, gamma-melanocyte stimulating hormone and perhaps other modified products of POMC. Thus well designed agonists and antagonists of these ligands might serve as drugs for the treatment of feeding disorders. However, these melanotropin peptides also can have other biological activities that involve the MC3R and MC4R, and these other biological properties will need to be modulated in ligands that are likely to be useful drugs for feeding disorders. Current progress in these areas with special emphasis on the MC3R will be discussed along with possible new directions that might be fruitful in these important aspects of contemporary biology and medicine.
Cai
Minying
M
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
Nyberg
Joel
J
Hruby
Victor J
VJ
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D009748:Nutrition Disorders / Q000188:drug therapy* / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D009074:Melanocyte-Stimulating Hormones
Nat Genet. 2000 Sep;26(1):97-102
10973258
Am J Physiol Regul Integr Comp Physiol. 2004 Mar;286(3):R417-30
14761863
Neuroimmunomodulation. 1996 Sep-Oct;3(5):259-84
9218248
Hypertension. 1987 Dec;10(6):619-27
3692573
J Pharmacol Exp Ther. 2008 Jun;325(3):927-34
18322151
J Med Chem. 2003 Aug 14;46(17):3728-33
12904077
Diabetes. 2007 Oct;56(10):2622-30
17639020
J Immunol. 2003 Mar 15;170(6):3323-30
12626592
J Neurosci. 1999 Sep 15;19(18):RC26
10479719
Am J Physiol. 1998 Apr;274(4):R931-8
9575953
J Med Chem. 2002 Jun 6;45(12):2644-50
12036373
Curr Top Med Chem. 2007;7(11):1098-1106
17584130
Curr Top Med Chem. 2007;7(11):1107-19
17584128
Biochem Pharmacol. 2007 Aug 1;74(3):383-91
17572390
J Med Chem. 1987 Nov;30(11):2126-30
2822931
Endocrinology. 2000 Sep;141(9):3518-21
10965927
Peptides. 2006 Feb;27(2):259-64
16274853
J Leukoc Biol. 2001 Jan;69(1):98-104
11200074
J Med Chem. 2000 Dec 28;43(26):4998-5002
11150170
J Med Chem. 2005 Mar 24;48(6):1839-48
15771429
Bioorg Med Chem Lett. 2006 Oct 15;16(20):5462-7
16931008
Endocrinology. 1972 Mar;90(3):700-6
5009346
Urology. 2000 Oct 1;56(4):641-6
11018622
J Neurosci. 1996 Aug 15;16(16):5182-8
8756446
J Med Chem. 1995 Sep 1;38(18):3454-61
7658432
Neuroscience. 1992;48(2):463-8
1318515
J Med Chem. 2008 Jan 24;51(2):187-95
18088090
Trends Pharmacol Sci. 2007 Dec;28(12):615-20
18022255
Nature. 1997 Jan 9;385(6612):165-8
8990120
Curr Top Med Chem. 2007;7(11):1121-30
17584132
J Clin Endocrinol Metab. 2004 Aug;89(8):3936-42
15292330
Arthritis Rheum. 2002 Oct;46(10):2765-75
12384937
J Pharmacol Exp Ther. 2005 Jan;312(1):382-90
15333678
ACS Chem Biol. 2008 Sep 19;3(9):530-41
18652471
Peptides. 2005 Aug;26(8):1481-5
15876475
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4867-72
12663858
Recept Channels. 2002;8(5-6):261-8
12690954
J Med Chem. 2009 Jun 25;52(12):3627-35
19473029
J Neurosci. 2008 Nov 26;28(48):12946-55
19036988
Curr Neuropharmacol. 2007 Sep;5(3):149-56
19305797
Nat Rev Drug Discov. 2009 Jan;8(1):41-54
19116626
Ann N Y Acad Sci. 2003 Jun;994:12-20
12851293
Am J Physiol. 1997 Jun;272(6 Pt 2):R1946-53
9227612
J Med Chem. 2006 Mar 23;49(6):1946-52
16539382
Am J Physiol. 1986 Jul;251(1 Pt 1):E134-7
3014888
Eur J Pharmacol. 1995 Dec 29;294(2-3):795-803
8750747
J Pept Res. 2004 Feb;63(2):116-31
15009533
Endocr Rev. 2006 Dec;27(7):736-49
17077189
Peptides. 2008 Mar;29(3):440-7
18155809
Gen Comp Endocrinol. 1989 Jan;73(1):157-63
2537778
Biochem Pharmacol. 2008 Aug 15;76(4):520-30
18614155
Endocrinology. 2006 May;147(5):2183-96
16469808
J Leukoc Biol. 2004 Oct;76(4):845-53
15277567
J Biol Chem. 2007 Jul 27;282(30):21712-9
17545153
Drug Discov Today. 2004 Sep 1;9(17):752-8
15450241
Obes Rev. 2003 Nov;4(4):239-48
14649374
Biochemistry. 2006 Jan 31;45(4):1128-37
16430209
Eur J Pharmacol. 2002 Nov 1;454(1):71-9
12409007
Eur J Pharmacol. 2001 Oct 19;429(1-3):61-9
11698027
Br J Pharmacol. 1997 Apr;120(8):1561-7
9113379
J Hypertens. 2006 Nov;24(11):2239-46
17053546
Curr Opin Pharmacol. 2003 Oct;3(5):551-6
14559102
J Urol. 1998 Aug;160(2):389-93
9679884
Nat Rev Drug Discov. 2002 Mar;1(3):198-210
12120504
Curr Opin Chem Biol. 2008 Jun;12(3):269-80
18342020
Nature. 2001 May 24;411(6836):480-4
11373681
Curr Pharm Des. 2004;10(17):2003-13
15279541
Pharmacol Rev. 2002 Jun;54(2):323-74
12037145
Naunyn Schmiedebergs Arch Pharmacol. 2002 Aug;366(2):177-82
12122505
Bioorg Med Chem Lett. 2007 May 1;17(9):2492-8
17314042