Stereochemical Studies on Medicinal Agents. 12. The Distinction of Enantiotopic Groups in the Interaction of l-Methyl-4-phenyl-4-propionoxypiperidine with Analgetic Receptors

Dennis L. Larson, Philip S Portoghese

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42 Citations (Scopus)

Abstract

The four optical isomers of α- and β-prodine have been prepared and their absolute stereochemistries determined by chemical correlation with (2R)-3-dimethylamino-2-methylpropiophenone. The sc analgetic ED50 values of the prodines in mice indicate that the two isomers which possess the 4S configurations are considerably more potent than their antipodes. This, coupled with the fact that the potency of 4-phenyl-4-propionoxy-1-methylpiperidine (5), a molecule with enantiotopic edges, is greater than that of the prodines having a 4R chiral center, suggests that the “Ogston effect” is operative in the interaction of 5 with analgetic receptors. It is proposed that the discrimination of the enantiotopic edges by the receptor is due to a combination of configurational and conformational factors.

Original languageEnglish (US)
Pages (from-to)195-198
Number of pages4
JournalJournal of Medicinal Chemistry
Volume16
Issue number3
DOIs
StatePublished - Mar 1 1973

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title = "Stereochemical Studies on Medicinal Agents. 12. The Distinction of Enantiotopic Groups in the Interaction of l-Methyl-4-phenyl-4-propionoxypiperidine with Analgetic Receptors",
abstract = "The four optical isomers of α- and β-prodine have been prepared and their absolute stereochemistries determined by chemical correlation with (2R)-3-dimethylamino-2-methylpropiophenone. The sc analgetic ED50 values of the prodines in mice indicate that the two isomers which possess the 4S configurations are considerably more potent than their antipodes. This, coupled with the fact that the potency of 4-phenyl-4-propionoxy-1-methylpiperidine (5), a molecule with enantiotopic edges, is greater than that of the prodines having a 4R chiral center, suggests that the “Ogston effect” is operative in the interaction of 5 with analgetic receptors. It is proposed that the discrimination of the enantiotopic edges by the receptor is due to a combination of configurational and conformational factors.",
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N2 - The four optical isomers of α- and β-prodine have been prepared and their absolute stereochemistries determined by chemical correlation with (2R)-3-dimethylamino-2-methylpropiophenone. The sc analgetic ED50 values of the prodines in mice indicate that the two isomers which possess the 4S configurations are considerably more potent than their antipodes. This, coupled with the fact that the potency of 4-phenyl-4-propionoxy-1-methylpiperidine (5), a molecule with enantiotopic edges, is greater than that of the prodines having a 4R chiral center, suggests that the “Ogston effect” is operative in the interaction of 5 with analgetic receptors. It is proposed that the discrimination of the enantiotopic edges by the receptor is due to a combination of configurational and conformational factors.

AB - The four optical isomers of α- and β-prodine have been prepared and their absolute stereochemistries determined by chemical correlation with (2R)-3-dimethylamino-2-methylpropiophenone. The sc analgetic ED50 values of the prodines in mice indicate that the two isomers which possess the 4S configurations are considerably more potent than their antipodes. This, coupled with the fact that the potency of 4-phenyl-4-propionoxy-1-methylpiperidine (5), a molecule with enantiotopic edges, is greater than that of the prodines having a 4R chiral center, suggests that the “Ogston effect” is operative in the interaction of 5 with analgetic receptors. It is proposed that the discrimination of the enantiotopic edges by the receptor is due to a combination of configurational and conformational factors.

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