Faculty Articles

Publication Title

Journal of Medicinal Chemistry

Publisher

American Chemical Society

ISSN

0022-2623

Publication Date

1-10-2019

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

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

DOI

10.1021/acs.jmedchem.8b00238

Volume

62

Issue

1

First Page

144

Last Page

158

Comments

This work has been supported by NIH Grant R01DK091906 (C.H.-L.). C.J.L. and A.T.Z. was provided support from the University of Minnesota Doctoral Dissertation Fellowship. C.J.L. was provided additional the University of Minnesota College of Pharmacy Olsteins Graduate Fellowship. We would also like to acknowledge the receipt of a 2017 Wallin Neuroscience Discovery Fund Award.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Download
Peer Reviewed

Find in your library

Share

COinS