1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization

Srinivasa R. Tala, Anamika Singh, Cody J. Lensing, Sathya M. Schnell, Katie T. Freeman, James R. Rocca, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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-NH 2 (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.

Original languageEnglish (US)
Pages (from-to)1001-1013
Number of pages13
JournalACS Chemical Neuroscience
Volume9
Issue number5
DOIs
StatePublished - May 16 2018

Bibliographical note

Funding Information:
*Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, 308 Harvard St. SE, Minneapolis, MN 55455. E-mail: chaskell@umn.edu. Phone: 612-626-9262. Fax: 612-626-3114. ORCID Carrie Haskell-Luevano: 0000-0002-6783-5972 Author Contributions S.R.T. and C.H.-L. designed the research. S.R.T., A.S., S.M.S., and K.T.F. performed the experiments. J.R.R. acquired NMR spectra. S.R.T., A.S., and C.H.-L. analyzed the data. S.R.T. wrote the manuscript with the help of A.S., C.J.L., and C.H.-L. Funding This work has been supported by National Institutes of Health Grant R01DK091906 (C.H.-L.). The authors also acknowledge the receipt of a 2017 Wallin Neuroscience Discovery Fund Award. Notes The authors declare no competing financial interest.

Funding Information:
The authors thank the National High Magnetic Field Laboratory, which is supported by National Science Foundation Cooperative Agreement DMR-1157490 and the State of Florida. The authors acknowledge Dr. Mark Ericson and Dr. Skye Doering for their aid in the preparation of the manuscript.

Keywords

  • AGRP
  • Melanocortin receptors
  • disulfide bond
  • peptidomimetic
  • triazoles

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