Identification of the first trans-(3R,4R)-dimethyl-4-(3- hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity:

A structurally novel opioid κ 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 κ receptor in the binding assay (κ Ki = 0.3 nM) and highly potent and selective κ antagonism in the [35S]GTP-γ-S assay using cloned opioid receptors (κ Ki = 0.006 nM, μ/κ ratio = 570, δ/κ ratio > 16600).