Journal of Biological Chemistry
Volume 277, Issue 16, 19 April 2002, Pages 13821-13826
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MECHANISMS OF SIGNAL TRANSDUCTION
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*

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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 Arg6 of hMCH, Ac-Arg6-cyclo(S-S)(Cys7-Met8-Leu9-Gly10-Arg11-Val12-Tyr13-Arg14-Pro15-Cys16)-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 variousd-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 withd-Arg in place of l-Arg in position 6 and Asn in place of Gly in position 10, Ac-dArg6-cyclo(S-S)(Cys7-Met8-Leu9-Asn10-Arg11-Val12-Tyr13-Arg14-Pro15-Cys16)-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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Published, JBC Papers in Press, February 11, 2002, DOI 10.1074/jbc.M200563200

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