S38151 [p-guanidinobenzoyl-[Des-Gly(10)]-MCH(7-17)] is a potent and selective antagonist at the MCH(1) receptor and has anti-feeding properties in vivo.
Structure-activity relationships studies have established the minimal sequence of melanin-concentrating hormone (MCH) that retains full agonist potency at the MCH(1), to be the dodecapeptide MCH(6-17). The alpha-amino function is not required for activity since arginine(6) can be replaced by p-guanidinobenzoyl, further improving activity. We report that the deletion of glycine in this short potent agonist (EC(50) 3.4nM) turns it into a potent and new MCH(1) antagonist (S38151, K(B) 4.3nM in the [(35)S]-GTPgammaS binding assay), which is selective versus MCH(2). A compared Ala-scan of the agonist and antagonist sequences reveals major differences in the residues that are mandatory for affinity, including arginine(11) and tyrosine(13) for the agonist and leucine(9) for the antagonist, whereas methionine(8) was necessary for both agonist and antagonist activities. A complete molecular study of the antagonist behavior is described in the present report, with a particular focus on the description of several analogues, attempting to find structure-activity relationships. Finally, S38151 antagonizes food intake when injected intra-cerebroventricularly in the rat. This is in agreement with the in vitro data and with our previous demonstration of a good correlation between in vitro and in vivo data on MCH(1) agonists.
Audinot
Valérie
V
Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, Croissy-sur-Seine, France.
Zuana
Odile Della
OD
Fabry
Nelly
N
Ouvry
Christine
C
Nosjean
Olivier
O
Henlin
Jean-Michel
JM
Fauchère
Jean-Luc
JL
Boutin
Jean A
JA
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005247:Feeding Behavior / Q000187:drug effects*; D006801:Humans; D007028:Hypothalamic Hormones / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D008543:Melanins / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010907:Pituitary Hormones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011979:Receptors, Pituitary Hormone / Q000819:agonists / Q000037:antagonists & inhibitors*
D007028:Hypothalamic Hormones; D008543:Melanins; D010455:Peptides; D010907:Pituitary Hormones; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; C019463:melanin-concentrating hormone