A new bicyclic template has been developed for the synthesis of peptide mimetics. Straightforward synthetic steps, starting from amino acids, allow the facile construction of a wide range of analogs. This system was designed to target the melanocortin receptors (MCRs), with functional group selection based on a known pharmacophore and guidance from molecular modeling to rationally identify positional and stereochemical isomers likely to be active. The functions of hMCRs are critical to myriad biological activities, including pigmentation, steroidogenesis, energy homeostasis, erectile activity, and inflammation. These G-protein-coupled receptors (GPCRs) are targets for drug discovery in a number of areas, including cancer, pain, and obesity therapeutics. All compounds from this series tested to date are antagonists which bind with high affinity. Importantly, many are highly selective for a particular MCR subtype, including some of the first completely hMC5R-selective antagonists reported.
The human melanocortin receptors (hMCRs) comprise a family of 5 Type I, or rhodopsin-like, G-protein-coupled receptors (GPCRs) to which a wide array of biological functions has been ascribed. Some examples include nociception, inflammation, energy balance, and sexual function. From the early understanding of the role MCRs play in pigmentation to recent revelations concerning their relevance to pain, new studies have continually uncovered crucial but previously unknown actions of this receptor system. Beyond advancing our knowledge of basic biology, the understanding and modulation of MCR function also has clinical relevance, with potential therapeutic value for addressing obesity, cachexia, pain,* inflammatory diseases, and sexual dysfunction, as well as the diagnosis and treatment of certain cancers.
Much research to date has relied on natural and synthetic peptide ligands for these receptors. The MCRs are unique in that both endogenous agonists (?-, ?-, ?-MSH, ACTH) and antagonists (agouti, AGRP) for the system have been discovered. Each of the agonists contains the His-Phe-Arg-Trp tetrad, the minimum sequence necessary for activation of all melanocortin receptors. Both endogenous antagonists contain an Arg-Phe-Phe sequence. Extensive melanotropin peptide structure–activity relationship (SAR) studies by our group and others have identified modifications which enhance potency, stability, or selectivity. The value of the ligands generated—particularly the standard agonists NDP-?-MSH and MT-II (Melanotan 2), and the antagonist, SHU9119, is hard to overestimate.
Nevertheless, with respect to certain applications in biology and medicine, the possession of small molecules with activity at the MCRs and properties complementary to those of peptides would be advantageous. Considerable effort in both academic and industrial laboratories has been directed toward this end. Successful examples have come from screening libraries, ‘privileged structure’ design strategies, and ligand-based rational design using computational chemistry.
We decided to employ this latter modeling approach to guide our design of small molecule peptide mimetics. Careful consideration of potential molecular scaffolds for ?-turn mimetics led us to the bicyclic structure. From a synthetic point of view, compounds of this type are easily constructed from amino acids, allowing us to take advantage both of the naturally available chiral pool and our group's extensive repertoire of unnatural amino acid syntheses.
The functional groups appended to our template were chosen based on SAR both for peptide ligands and previous MCR-targeted small molecules. Peptides active at all five MCRs contain the His-Phe-Arg-Trp sequence, while the minimum chemical features seemingly common to all active small molecules are the presence of two hydrophobic aromatic groups and a basic nitrogen. The most widely expressed of the MCRs, the MC5R has been linked to energy homeostasis and thermoregulation.
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