Discovery of μ-opioid selective ligands derived from 1-aminotetralin scaffolds made via metal-catalyzed ring-opening reactions

A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)–(S)-5.2a as a high-affinity selective μ ligand (IC50μ = 5 nM, κ = 707 nM, δ = 3,795 nM) displaying μ-agonist/antagonist properties due to its partial agonism (EC50 = 2.6 μM; Emax = 18%).

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