Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

Melanin-concentrating hormone (MCH) is a 19-amino-acid cyclic peptide which was originally found to lighten skin color in fish that is highly conserved among many species. MCH interacts with two G-protein-coupled receptors, MCH1R and MCH2R, but only MCH1R is expressed in rodents. MCH is mainly synthesized in the lateral hypothalamus and zona incerta, while MCH1R is widely expressed throughout the brain. Thus, MCH signaling is implicated in the regulation of many physiological functions. The identification of MCH1R has led to the development of small-molecule MCH1R antagonists that can block MCH signaling. MCH1R antagonists are useful not only for their potential therapeutic value, but also for understanding the physiological functions of the endogenous MCH system. Here, we review the physiological functions of the MCH system which have been investigated using MCH1R antagonists such as food intake, anxiety, depression, reward, and sleep. This will help us understand the physiological functions of the MCH system and suggest some of the potential applications of MCH1R antagonists in human disorders

Synthesis and in vitro and in vivo characterization of highly β1-Selective β-Adrenoceptor partial agonists

β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1- selectivity

Biological diversity from a structurally diverse library: Systematically scanning conformational space using a pyranose scaffold

Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH1) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping