cn7b00422_si_001.pdf (1.28 MB)
1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization
journal contribution
posted on 2017-12-19, 00:00 authored by Srinivasa R. Tala, Anamika Singh, Cody J. Lensing, Sathya M. Schnell, Katie T. Freeman, James R. Rocca, Carrie Haskell-LuevanoThe 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.