Simple Tetrahydroisoquinolines Are Potent and Selective Kappa Opioid Receptor Antagonists

Kormos, C. M., Ondachi, P. W., Runyon, S. P., Thomas, J. B., Mascarella, S. W., Decker, A. M., ... Carroll, F. I. (2017). Simple Tetrahydroisoquinolines Are Potent and Selective Kappa Opioid Receptor Antagonists. ACS Medicinal Chemistry Letters, 8(7), 742-745. DOI: 10.1021/acsmedchemlett.7b00115

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.