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

Structure–activity relationships studies have established the minimal sequence of melanin-concentrating hormone (MCH) that retains full agonist potency at the MCH1, to be the dodecapeptide MCH(6-17). The α-amino function is not required for activity since arginine6 can be replaced by p-guanidinobenzoyl, further improving activity. We report that the deletion of glycine in this short potent agonist (EC50 3.4 nM) turns it into a potent and new MCH1 antagonist (S38151, KB 4.3 nM in the [35S]-GTPγS binding assay), which is selective versus MCH2. A compared Ala-scan of the agonist and antagonist sequences reveals major differences in the residues that are mandatory for affinity, including arginine11 and tyrosine13 for the agonist and leucine9 for the antagonist, whereas methionine8 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 MCH1 agonists.