The superfamily of the GPCRs can be classified into the somatosensory GPCRs (500-700 members) and “transmitter” (about 360 members) GPCRs. These last GPCRs bind all the known neurotransmitters, neuropeptides and peptide hormones and are the omnipresent modulators of brain function. Of the 360 transmitter GPCRs, 260 bind known ligands, while the others bind ligands that have not been thus far described. These are the orphan GPCRs, which carry the promise to lead us to the discovery of novel physiological responses. However, orphan GPCR research is hampered by the lack of these receptors natural ligands. To be studied, orphan GPCRs need to be deorphanized, i.e. their natural ligand need to be characterized. We have devised a strategy to identify the natural ligands of orphan GPCRs. We use expressed orphan GPCRs as a targets and tissue extracts as source of their natural ligands. Since 1995, this strategy has led to the discovery of 10 novel transmitter families. The novel transmitters have been studied for their pharmacological characteristics, for the localizations of their sites of expression and sites of action in the CNS and for their functional roles. This has led to a broadening of our understanding of particular physiological functions. For example, the first transmitter to be discovered via the orphan receptor strategy, Orphanin FQ/Nociceptin, has shown to be of great interest to neurosciences. It is foreseen that most of the other novel transmitters will follow this path. Interestingly, several of the novel neuropeptides discovered as ligands of orphan GPCRs exhibit regulatory roles on food intake (1). The behavioral response to food intake rests on a balance between orexigenic and anorexigenic signals. The regulation of this balance starts in the periphery, reaches the arcuate nucleus and ultimately converges onto the lateral hypothalamus. The regulatory role of the lateral hypothalamus is thought to be carried out by two ligands of orphan GPCRs, the neuropeptides orexins and melanin-concentrating hormone (MCH). To understand the functional significance of the MCH system, we have isolated a synthetic MCH receptor antagonist. This antagonist was identified through the screening of synthetic combinatorial libraries. The antagonist inhibits MCH-induced Ca2+ mobilization with an IC50 value of 6 nM for and is specific for the MCH1R. When administered i.c.v., it blocks spontaneous food intake in a dose dependent manner. However, it has only a weak and transient inhibitory effect on food intake. On the other hand, when administered peripherally, it reduces nocturnal food intake and induces significant metabolic changes. Using this selective antagonist we thus can differentiate the central and peripheral effects of the MCH system.