ISBN or ISSN
Journal of Medicinal Chemistry
Publication Date / Copyright Date
American Chemical Society
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
Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences
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
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.