The
melanocortin system is involved in the regulation of complex physiological functions, including energy and weight homeostasis, feeding behavior,
inflammation, sexual function, pigmentation, and exocrine gland function. The five
melanocortin receptors that belong to the superfamily of
G protein-coupled receptors (GPCRs) are regulated by endogenously expressed agonists and antagonists. The aim of this study was to explore the potential of replacing the
disulfide bridge in chimeric AGRP-
melanocortin peptide Tyr-c[Cys-His-d-
Phe-Arg-Trp-Asn-
Ala-Phe-
Cys]-Tyr-NH2 (1) with 1,2,3-triazole moieties. A series of 1,2,3-triazole-bridged
peptidomimetics were designed, synthesized, and pharmacologically evaluated at the mouse
melanocortin receptors. The
ligands possessed nanomolar to micromolar agonist cAMP signaling potency. A key finding was that the
disulfide bond in
peptide 1 can be replaced with the monotriazole ring with minimal effect on the functional activity at the
melanocortin receptors. The 1,5-disubstituted
triazole-bridged
peptide 6 showed equipotent functional activity at the mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared to those of 1. Interestingly, the 1,4- and 1,5-disubstituted isomers of the
triazole ring resulted in different selectivities at the receptor subtypes, indicating subtle structural features that may be exploited in the generation of selective
melanocortin ligands. Introducing cyclic and acyclic bis-
triazole moieties into chimeric AGRP template 1 generally decreased agonist activity. These results will be useful for the further design of neuronal chemical probes for the
melanocortin receptors as well as in other receptor systems.