title: 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.
abstract: 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))-NH(2), Ac-hMCH(6-16)-NH(2), 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)-NH(2) 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))-NH(2), was a potent hMCH-1R agonist (IC(50) = 0.5 nm, EC(50) = 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. maria_bednarek@merck.com
authors.forename: Maria A
authors.initials: MA
authors.lastname: Bednarek
authors.forename: Carina
authors.initials: C
authors.lastname: Tan
authors.forename: Donna L
authors.initials: DL
authors.lastname: Hreniuk
authors.forename: Oksana C
authors.initials: OC
authors.lastname: Palyha
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: MacNeil
authors.forename: Lex H Y
authors.initials: LH
authors.lastname: Van Der Ploeg
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Scott D
authors.initials: SD
authors.lastname: Feighner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007028:Hypothalamic Hormones / Q000819:agonists* / Q000737:chemistry*; D066298:In Vitro Techniques; D008024:Ligands; D008543:Melanins / Q000819:agonists* / Q000737:chemistry*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry; D010907:Pituitary Hormones / Q000819:agonists* / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone / Q000737:chemistry*
chemical_list: D007028:Hypothalamic Hormones; D008024:Ligands; C431280:MCHR2 protein, human; D008543:Melanins; D010455:Peptides; D010907:Pituitary Hormones; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; C019463:melanin-concentrating hormone; D002118:Calcium