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
| Autor: | Sathya M. Schnell, Cody J. Lensing, Adam T. Zarth, Carrie Haskell-Luevano, Robert C. Speth, Katie T. Freeman |
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| Rok vydání: | 2018 |
| Předmět: |
Agonist
Bioluminescence Resonance Energy Transfer Techniques Models Molecular medicine.drug_class Allosteric regulation Ligands 01 natural sciences Article 03 medical and health sciences Melanocortin receptor Allosteric Regulation Drug Discovery Functional selectivity medicine Cyclic AMP Humans 030304 developmental biology G protein-coupled receptor 0303 health sciences Chemistry Receptors Melanocortin beta-Arrestin 2 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry HEK293 Cells Drug Design Molecular Medicine Melanocortin Signal transduction Pharmacophore Dimerization Signal Transduction |
| Zdroj: | Journal of medicinal chemistry. 62(1) |
| ISSN: | 1520-4804 |
| Popis: | 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(50) ~ 2 to 6 nM), but minimally activating the β-arrestin recruitment pathway (≤55% maximum signal at 10 µM). To our knowledge, we report the first single-compound strategy to pharmacologically target melanocortin receptor allosteric signaling that occurs between homodimers that can be applied straightforwardly in vitro and in vivo to other GPCR systems. |
| Databáze: | OpenAIRE |
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