Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "unbiased" Screening Campaign

Skye R. Doering, Katie Freeman, Ginamarie Debevec, Phaedra Geer, Radleigh G. Santos, Travis M. Lavoi, Marc A. Giulianotti, Clemencia Pinilla, Jon R. Appel, Richard A. Houghten, Mark D. Ericson, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

Abstract

The central melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are key regulators of body weight and energy homeostasis. Herein, the discovery and characterization of first-in-class small molecule melanocortin agonists with selectivity for the melanocortin-3 receptor over the melanocortin-4 receptor are reported. Identified via "unbiased"mixture-based high-throughput screening approaches, pharmacological evaluation of these pyrrolidine bis-cyclic guanidines resulted in nanomolar agonist activity at the melanocortin-3 receptor. The pharmacological profiles at the remaining melanocortin receptor subtypes tested indicated similar agonist potencies at both the melanocortin-1 and melanocortin-5 receptors and antagonist or micromolar agonist activities at the melanocortin-4 receptor. This group of small molecules represents a new area of chemical space for the melanocortin receptors with mixed receptor pharmacology profiles that may serve as novel lead compounds to modulate states of dysregulated energy balance.

Original languageEnglish (US)
Pages (from-to)5577-5592
Number of pages16
JournalJournal of medicinal chemistry
Volume64
Issue number9
DOIs
StatePublished - May 13 2021

Bibliographical note

Funding Information:
This work was supported in part by NIH R01 grants R01DK091906 (C.H.-L.), and R01DA031370 (R.A.H.), the State of Florida, and the Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development (R.A.H.). The authors would also like to acknowledge the receipt of a 2017 Wallin Neuroscience Discovery Fund Award and Engebretson Drug Design and Development Grant (C.H.-L.).

Publisher Copyright:
© 2021 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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