Developing a Biased Unmatched Bivalent Ligand (BUmBL) Design Strategy to Target the GPCR Homodimer Allosteric Signaling (cAMP over β-Arrestin 2 Recruitment) Within the Melanocortin Receptors

Cody J. Lensing, Katie T. Freeman, Sathya M. Schnell, Robert C. Speth, Adam T. Zarth, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore. First-in-class biased UmBLs (BUmBLs) targeting the human melanocortin-4 receptor (hMC4R) were discovered. The BUmBLs displayed biased agonism by potently stimulating cAMP signaling (EC 50 ∼ 2-6 nM) but minimally activating the β-arrestin recruitment pathway (≤55% maximum signal at 10 μM). To our knowledge, we report the first single-compound strategy to pharmacologically target melanocortin receptor allosteric signaling that occurs between homodimers that can be applied straightforwardly in vitro and in vivo to other GPCR systems.

Original languageEnglish (US)
Pages (from-to)144-158
Number of pages15
JournalJournal of medicinal chemistry
Volume62
Issue number1
DOIs
StatePublished - Jan 10 2019

PubMed: MeSH publication types

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

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