PHENYLMORPHANS AND ANALOGS - 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 attentuated 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.