Phenylmorphans and Analogues: Opioid Receptor Subtype Selectivity and Effect of Conformation on Activity

Mark Froimowitz, Chaim G. Pick, Gavril W. Pasternak

Research output: Contribution to journalArticlepeer-review

Abstract

The morphine-like (+)-phenylmorphan, the atypical (-)-enantiomer, and some analogues have been tested in receptor binding assays selective for opioid μ1, μ2,δ, k1, and k3 receptors. The affinities of all of the compounds except one, including the atypical (-)-phenylmorphan, were greatest for μ1 and μ2 receptors. The only exception was the (+)-9α-methyl analogue which had slightly greater affinity for the k1 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 μ 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 β-FNA (μ1 and μ2, naloxonazine (μ1), nor-BNI (k1), and naltrindole (δ) suggests that the antinociceptive activity of both enantiomers is mediated through μ receptors. The pretreatment with naloxonazine, which attentuated the antinociceptive effect, shows that both (+)-and (-)-phenylmorphan are μ1 agonists while intrathecal administration shows that both are μ2 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.

Original languageEnglish
Pages (from-to)1521-1525
Number of pages5
JournalJournal of Medicinal Chemistry
Volume35
Issue number9
DOIs
StatePublished - 1 May 1992
Externally publishedYes

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