Simple Tetrahydroisoquinolines Are Potent and Selective Kappa Opioid Receptor Antagonists.

Potent and selective κ 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, (3 R )-7-hydroxy- N -[(1 S )-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 (3 R )- N -(1 R )-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 [35 S]GTPγS binding properties at the μ, δ, and κ opioid receptors. Surprisingly compound 1 remained a pure opioid antagonist with a K e = 6.80 nM at the κ opioid receptor and is 21- and 441-fold selective for the κ receptor relative to the μ and δ opioid receptors, respectively. Even more unexpected and novel is the finding that 2 has a K e = 0.14 nM at κ and is 1730- and 4570-fold selective for κ relative to the μ and δ opioid receptors, respectively.