Synthesis and In Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa Opioid Receptor Antagonist (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)

In previous structure–activity relationship (SAR) studies, we identified (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, 1) as the first potent and selective κ opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [35S]GTPγS binding assay. The results from the studies better define the pharmacophore for this class of κ opioid receptor antagonist and has identified new potent and selective κ antagonist. (3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3) with a Ke value of 0.03 nM at the κ receptor and 100- and 793-fold selectivity relative to the μ and δ receptors was the most potent and selective κ opi...