Year: 2024
Type: article
Abstract: , is an agonist of the kappa opioid receptor (κOR). To establish structure-activity relationships (SARs) for this structurally unique κOR ligand, a collection of semisynthetic derivatives was synthesized. Evaluating these derivatives for their ability to activate the κOR and mu opioid receptor (μOR) revealed key SAR trends and identified derivatives with enhanced κOR potency. Most notably, substitutions to the C10 position of the aryl ring led to a > 200-fold improvement in κOR potency and nearly complete selectivity for the κOR. A selection of the most potent ligands was shown to possess differing abilities recruitment of β-Arrestin-2 to the κOR, indicating they have distinct signaling properties from each other and existing κOR ligands. The discovery of these κOR agonists underscores the potential of using natural products to identify new classes of potent and selective ligands and provides new tools to probe the κOR.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: American Foundation for Pharmaceutical Education, National Institutes of Health, University of North Carolina at Chapel Hill, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Center for Advancing Translational Sciences, National Center for Complementary and Integrative Health
Awards: G162808528, Development of G-protein biased delta opioid receptor agonist with analgesic potency, G229319214, G3142225666, G3201181780, G3423045826, G4082710959, G4118060598, G4307468187, G76741582, G8691474425, G9000013398, G9000221889, G9000333052, Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors, Aristotelia Alkaloids as Probes for the Nicotinic Acetylcholine Receptors
OpenAlex ID: W4404567946