Phenylmorphans and analogues: opioid receptor subtype selectivity and effect of conformation on activity

The morphine-like (+)-phenylmorphan, the atypical (-)-enantiomer, and some analogues have been tested in receptor binding assays selective for opioid mu 1, mu 2, delta, kappa 1, and kappa 3 receptors. The affinities of all of the compounds except one, including the atypical (-)-phenylmorphan, were greatest for mu 1 and mu 2 receptors. The only exception was the (+)-9 alpha-methyl analogue which had slightly greater affinity for the kappa 1 receptor. The selective receptor binding assays provide evidence that opioids in which the phenyl ring is constrained to be equatorial on the piperidine ring can have considerable affinity for mu receptors. In addition, dose-response curves were determined for (+)- and (-)-phenylmorphan using the mouse tail-flick assay with the (+)-enantiomer found to be about 7 times more potent. Pretreatment with the selective opioid antagonists beta-FNA (mu 1 and mu 2), naloxonazine (mu 1), nor-BNI (kappa 1), and naltrindole (delta) suggests that the antinociceptive activity of both enantiomers is mediated through mu receptors. The pretreatment with naloxonazine, which attenuated the antinociceptive effect, shows that both (+)- and (-)-phenylmorphan are mu 1 agonists while intrathecal administration shows that both are mu 2 agonists. Conformational energy calculations on the compounds were also performed using the MM2-87 program. Consistent with previous conformational results for the phenylmorphans (J. Med. Chem. 1984, 27, 1234-1237), the most potent antinociceptive compounds preferred a particular orientation of the phenyl ring.