Vol. 299, Issue 1, 137-146, October 2001

SLC-1 Receptor Mediates Effect of Melanin-Concentrating Hormone on Feeding Behavior in Rat: A Structure-Activity Study

Thomas Suply , Odile Della Zuana, Valérie Audinot, Marianne Rodriguez, Philippe Beauverger, Jacques Duhault, Emmanuel Canet, Jean-Pierre Galizzi, Jean-Louis Nahon, Nigel Levens and Jean A. Boutin

Division de Pharmacologie Moleculaire et Cellulaire, Institut de Recherches Servier, Croissy/Seine, France (T.S., V.A., M.R., P.B., E.C., J.-P.G., J.A.B.); Division Métabolisme, Institut de Recherches Servier, Suresnes, France (O.D.Z., J.D., N.L.); and Institut de Pharmacologie Moleculaire et Cellulaire, Unité Mixte de Recherche Center National de la Recherche Scientifique, Valbonne-Sophia-Antipolis, France (T.S., J.-L.N.)

Several studies have shown that melanin-concentrating hormone (MCH) is an orexigenic peptide in rat. In the present study, a structure-activity relationship with MCH analogs was performed in rat, both in vitro and in vivo. On rat recombinant SLC-1 receptor, both cAMP inhibition and [¹²⁵I]S36057 binding were measured. In vivo, these analogs were injected intracerebroventricularly in rats and their effects were evaluated upon food intake. First, data obtained with the rat recombinant receptor were highly correlated with those obtained from its human counterpart. Second, agonist potencies in the cAMP assay were also highly correlated with binding affinities. These peptides could be classified into several groups according to their potency at the SLC-1 receptor (from subnanomolar activity to complete inactivity). Indeed, there was a strong correlation between their effects upon food intake and the results obtained at the rat SLC-1 receptor. The present report describes for the first time the rat SLC-1 receptor pharmacology and clearly establishes the relevance of the SLC-1 receptor in feeding behavior.