S38151 [p-guanidinobenzoyl-[Des-Gly10]-MCH(7-17)] is a potent and selective antagonist at the MCH1 receptor and has anti-feeding properties in vivo.

Abstract 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 α-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 3.4 nM) turns it into a potent and new MCH 1 antagonist (S38151, K B 4.3 nM in the [ 35 S]-GTPγS 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.