Past studies have shown that it has been difficult to discover and develop potent and selective kappa opioid receptor antagonists, particularly compounds having potential for clinical development. In this study, we present a structure-activity relationship (SAR) study of a recently discovered new class of tetrahydroisoquinoline kappa opioid receptor antagonists which led to (3R)-7-hydroxy-N-{(1S)-2-methyl-1-[(-4-methylpiperidine-1-yl)methyl]propyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (12) (4-Me-PDTic). Compound 12 had a K-e = 0.37 nM in a [S-35]GTP gamma S binding assay and was 645- and >8100-fold selective for the kappa relative to the mu and delta opioid receptors, respectively. Calculated log BB and CNS (central nervous system) multiparameter optimization (MPO) and low molecular weight values all predict that 12 will penetrate the brain, and pharmacokinetic studies in rats show that 12 does indeed penetrate the brain.
