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

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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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Alphaprodine
Morphine
X-Rays

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title = "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",
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.",
author = "Portoghese, {Philip S} and Gomaa, {Zeinab S.D.} and Larson, {Dennis L.} and Eli Shefter",
year = "1973",
month = "3",
day = "1",
doi = "10.1021/jm00261a006",
language = "English (US)",
volume = "16",
pages = "199--203",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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T1 - 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

AU - Portoghese, Philip S

AU - Gomaa, Zeinab S.D.

AU - Larson, Dennis L.

AU - Shefter, Eli

PY - 1973/3/1

Y1 - 1973/3/1

N2 - 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.

AB - 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.

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