Identification of the First <i>trans</i>-(3<i>R</i>,4<i>R</i>)- Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative To Possess Highly Potent and Selective Opioid κ Receptor Antagonist Activity

Abstract

A structurally novel opioid kappa receptor selective ligand has been identified. This compound, (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 10) demonstrated high affinity for the kappa receptor in the binding assay (kappa K(i) = 0.3 nM) and highly potent and selective kappa antagonism in the [(35)S]GTP-gamma-S assay using cloned opioid receptors (kappa K(i) = 0.006 nM, mu/kappa ratio = 570, delta/kappa ratio > 16600).