Faculty Articles

Title

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.

Publication Title

Journal of medicinal chemistry

Volume

62

Issue

1

Publication Date / Copyright Date

1-10-2019

First Page

144

Last Page

158

Publisher

American Chemical Society

DOI Number

10.1021/acs.jmedchem.8b00238

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

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

Allosteric Regulation, Bioluminescence Resonance Energy Transfer Techniques, Cyclic AMP, Dimerization, Drug Design, HEK293 Cells, Humans, Ligands, Models, Molecular, Receptors, Melanocortin, Signal Transduction, beta-Arrestin 2

Peer Reviewed

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