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Full-Text Articles in Medicine and Health Sciences
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 Charles Speth, Adam T Zarth, Carrie Haskell-Luevano
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 Charles Speth, Adam T Zarth, Carrie Haskell-Luevano
Faculty Articles
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
An In Vitro And In Vivo Investigation Of Bivalent Ligands That Display Preferential Binding And Functional Activity For Different Melanocortin Receptor Homodimers, Cody J Lensing, Katie T Freeman, Sathya M Schnell, Danielle N Adank, Robert Charles Speth, Carrie Haskell-Luevano
An In Vitro And In Vivo Investigation Of Bivalent Ligands That Display Preferential Binding And Functional Activity For Different Melanocortin Receptor Homodimers, Cody J Lensing, Katie T Freeman, Sathya M Schnell, Danielle N Adank, Robert Charles Speth, Carrie Haskell-Luevano
Faculty Articles
Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds, suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 possessed a functional profile …