Stereochemical Studies on Medicinal Agents. 13. Correlation of the Solid-State Conformations of 1,3,5-Trimethyl- and 1,3-Dimethyl-4-phenyl-4-propionoxypiperidine Enantiomers with Their Absolute Stereoselectivity at Analgetic Receptors

Philip S. Portoghese, Zeinab S.D. Gomaa, Dennis L. Larson, Eli Shefter

Research output: Contribution to journalArticle

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Abstract

Optical antipodes of γ-1,3,5-trimethyl-4-phenyl-4-propionoxypiperidine (4) were prepared and the absolute configuration was determined by degradation to (R)-3-dimethylamino-2-methylpropiophenone. Analgetic testing in mice by the sc route indicated that the (+)-3S,5S isomer is equipotent with morphine and five times more potent than its (-) antipode. X-Ray studies of 4 · HCl indicate that the conformational features of the more active enantiomers of 4· HCl and α- and β-prodine HCl are very similar. It is suggested that the methyl groups adjacent to the C-4 center in the more active enantiomers of 4 and the prodines induce a preferred, chiral arrangement of the phenyl and OCO groups which allow more facile association with analgetic receptors.

Original languageEnglish (US)
Pages (from-to)199-203
Number of pages5
JournalJournal of medicinal chemistry
Volume16
Issue number3
DOIs
StatePublished - Mar 1 1973

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