The central effect of MCH system studied using a specific MCH 1R antagonist isolated from combinatorial libraries

Abstract

Melanin-concentrating hormone (MCH) is a neuropeptide that is prominently expressed in the lateral hypothalamus and that, when centrally administered, exhibits orexigenic properties. To better understand the functional significance of this system, we have isolated a specific MCH 1R antagonist, TPI 1361-17. This antagonist was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL). It exhibits an IC50 value of 6.1nM for inhibition of MCH-induced Ca2+ mobilization and completely displaced the binding of [125I]MCH to rat MCH1R. TPI 1361-17 is specific, having no affinity for a variety of other peptide GPCRs. We show that TPI 1361-17, administered icv, exhibits a dose-dependent but weak inhibitory effect on spontaneous food intake that is negated by starvation, suggesting that the primary role of the MCH system may not be to regulate food intake for its calorific value. On the other hand TPI 1361-17, when injected peripherally, reduces efficiently food intake. In particular, we show that TPI 1361-17 inhibits the development of diet-induced obesity and reduces body weight gain. Our results suggest that TPI 1361-17 is a novel and selective MCH1R antagonist that may serve to differentiate the central from the peripheral function of the MCH system.