Faculty Articles
ISBN or ISSN
0022-2623
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
NSUWorks Citation
Lensing, Cody J; Freeman, Katie T; Schnell, Sathya M; Speth, Robert Charles; Zarth, Adam T; and Haskell-Luevano, Carrie, "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." (2019). Faculty Articles. 113.
https://nsuworks.nova.edu/hpd_corx_facarticles/113
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.