Synthesis, X-Ray Crystallographic Determination, and Opioid Activity of erythro-5-Methylmethadone Enantiomers. Evidence Which Suggests That μ and δ Opioid Receptors Possess Different Stereochemical Requirements

P. S. Portoghese, J. H. Poupaert, D. L. Larson, W. C. Groutas, G. D. Meitzner, D. C. Swenson, G. D. Smith, W. L. Duax

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Abstract

Enantiomers of erythro-5-methylmethadone (3) were synthesized from optical antipodes of erythro-3-(dimethylamino)-2-butanol. X-ray crystallographic analysis of (−)-3 Perchlorate revealed that it possesses the 5S,6S absolute configuration. It was found that (−)-3 is substantially more potent than its enantiomer (+)-3 as an opioid agonist in vivo and in vitro. In vitro tests (guinea pig ileal longitudinal muscle and mouse vas deferens preparations) suggest that (−)-3 mediates its effect chiefly through μ opioid receptors. On the other hand, (+)-3 and the more potent enantiomers of methadone, (−)-1, and isomethadone, (−)-2, appear to have less μ-receptor selectivity and interact with a greater fraction of δ receptors than does (−)-3. The fact that the solid-state conformation of (−)-3 differs from that of (−)-1 and (−)-2, which show great similarity in conformational features, suggests that μ and δ receptors have different conformational requirements. The possibility of different modes of interaction with a single opioid receptor population also is discussed.

Original languageEnglish (US)
Pages (from-to)684-688
Number of pages5
JournalJournal of medicinal chemistry
Volume25
Issue number6
DOIs
StatePublished - 1982

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