Synthesis and biological evaluation in vitro of a selective, high potency peptide agonist of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1

被引:24
作者
Bednarek, MA
Tan, C
Hreniuk, DL
Palyha, OC
MacNeill, DJ
Van der Ploeg, LHY
Howard, AD
Feighner, SD
机构
[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Obes & Metab Disorders, Rahway, NJ 07065 USA
关键词
D O I
10.1074/jbc.M200563200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Human melanin-concentrating hormone (hMCH) is a nonselective natural ligand for the human melanin-concentrating hormone receptors: hMCH-1R and hMCH-2R. Similarly, the smaller peptide encompassing the disulfide ring and Arg(6) of hMCH, Ac-Arg(6)-cyclo(S-S)(Cys(7)-Met(8)-Leu(9)-Gly(10)-Arg(11)-Val(12)-Tyr(13)-Arg(14)-Pro(15)-Cys(16)).-NH2, Ac-hMCH(6-16)-NH2, binds to and activates equally well both human MCH receptors present in the brain. To separate the physiological functions of hMCH-1R from those of hMCH-2R, new potent and hMCH-1R selective agonists are necessary. In the present study, analogs of Ac-hMCH(6-16)-NH2 were prepared and tested in binding and functional assays on cells expressing the MCH receptors. In these peptides, Arg in position 6 was replaced with various D-amino acids and/or Gly in position 10 was substituted with various L-amino acids. Several of the new compounds turned out to be potent agonists at hMCH-1R with improved selectivity over hMCH-2R. For example, peptide 26 with D-Arg in place of L-Arg in position 6 and Asn in place of Gly in position 10, Ac-DArg(6)-cyclo(S-S)(Cys(7)-Met(8)-Leu(9)-Asn(10)-Arg(11)-Val(12)-Tyr(13)-Arg(14)-Pro(15)-Cys(16))-NH2, was a potent hMCH-1R agonist (IC50 = 0.5 nM, EC50 = 47 nM) with more than 200-fold selectivity with respect to hMCH-2R. Apparently, these structural changes in positions 6 and 10 results in peptide conformations that allow for efficient interactions with hMCH-1R but are unfavorable for molecular recognition at hMCH-2R.
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页码:13821 / 13826
页数:6
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