Simple tetrahydroisoquinolines are potent and selective kappa opioid receptor antagonists

Potent and selective kappa opioid receptor antagonists have been derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid receptor antagonists. In order to determine if the 3-hydroxyphenyl and/or the piperidine amino groups are required for obtaining the pure opioid antagonists, (3R)-7-hydroxy-N-[(1S)-2-methy1-1(piperidine- 1-ylmethyl) propyl]-1,2,3,4-tetrahydroiosquinoline-3-carboxamide (1), which does not have a 4-(3-hydroxyphenyl) group, and (3R)-N(1R)-1-(cydohexylmethyl)-2-methylpropy1]-7-hydroxy-1,2,3,4-tetrahydroiso-quinoline-3-carboxamide (2), which does not have a 4-hydroxylphenyl or a piperidine amino group, were synthesized and evaluated for their [S-35]GTP gamma S binding properties at the mu, delta, and kappa opioid receptors. Surprisingly compound 1 remained a pure opioid antagonist with a K-e = 6.80 nM at the kappa opioid receptor and is 21- and 441-fold selective for the kappa receptor relative to the mu and 6 opioid receptors, respectively. Even more unexpected and novel is the finding that 2 has a K-e = 0.14 nM at kappa and is 1730- and 4570-fold selective for kappa relative to the mu and delta opioid receptors, respectively.