Simple Tetrahydroisoquinolines Are Potent and Selective Kappa Opioid Receptor Antagonists.

ABSTRACT: Potent and selective ? 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-methyl-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-(cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2), which does not have a 4-hydroxylphenyl or a piperidine amino group, were synthesized and evaluated for their [35S]GTP?S binding properties at the ?, ?, and ? opioid receptors. Surprisingly compound 1 remained a pure opioid antagonist with a Ke = 6.80 nM at the ? opioid receptor and is 21- and 441-fold selective for the ? receptor relative to the ? and ? opioid receptors, respectively. Even more unexpected and novel is the finding that 2 has a Ke = 0.14 nM at ? and is 1730- and 4570-fold selective for ? relative to the ? and ? opioid receptors, respectively.

SUBMITTER: Kormos CM 

PROVIDER: S-EPMC5512122 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature