Stereochemical Studies on Medicinal Agents. 20. Absolute Configuration and Analgetic Potency of α-Promedol Enantiomers. The Role of the C-4 Chiral Center in Conferring Stereoselectivity in Axial- and Equatorial-Phenylprodine Congeners

David S. Fries, Philip S Portoghese

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Abstract

Optical antipodes of the axial phenyl analgetic, α-promedol hydrochloride (3), were prepared and the absolute stereochemistry was determined by relating one of the enantiomers to its γ diastereomer having the 2S,4S,5R configuration. The analgetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, while its enantiomer, (-)-(2S,4R,5R)-3, is inactive at 50 mg/kg. These results are in accord with prior reports which indicate that substitution of a 3- or 5-alkyl group on the pro-4S enantiotopic edge of the piperidine ring leads to enantiomers which have greater potency than those substituted in an identical position on the pro-4R edge. This, coupled with the fact that the torsion angle between the axial phenyl group and piperidine ring in (+)-3 is of the same sign as its equatorial congeners, suggests that the C(3)-C(4)-C(5) moiety and its substituents at C(4) are located in a similar chiral environment on the receptor. In contrast, the C(2)-N-C(6) portion of the axial and equatorial molecules does not bind in the same receptor environment, and it is suggested that different modes of interaction in the prodine series arise from different orientations of this moiety.

Original languageEnglish (US)
Pages (from-to)1155-1158
Number of pages4
JournalJournal of Medicinal Chemistry
Volume19
Issue number9
DOIs
StatePublished - Sep 1 1976

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Promedol
Alphaprodine
Morphine
piperidine

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title = "Stereochemical Studies on Medicinal Agents. 20. Absolute Configuration and Analgetic Potency of α-Promedol Enantiomers. The Role of the C-4 Chiral Center in Conferring Stereoselectivity in Axial- and Equatorial-Phenylprodine Congeners",
abstract = "Optical antipodes of the axial phenyl analgetic, α-promedol hydrochloride (3), were prepared and the absolute stereochemistry was determined by relating one of the enantiomers to its γ diastereomer having the 2S,4S,5R configuration. The analgetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, while its enantiomer, (-)-(2S,4R,5R)-3, is inactive at 50 mg/kg. These results are in accord with prior reports which indicate that substitution of a 3- or 5-alkyl group on the pro-4S enantiotopic edge of the piperidine ring leads to enantiomers which have greater potency than those substituted in an identical position on the pro-4R edge. This, coupled with the fact that the torsion angle between the axial phenyl group and piperidine ring in (+)-3 is of the same sign as its equatorial congeners, suggests that the C(3)-C(4)-C(5) moiety and its substituents at C(4) are located in a similar chiral environment on the receptor. In contrast, the C(2)-N-C(6) portion of the axial and equatorial molecules does not bind in the same receptor environment, and it is suggested that different modes of interaction in the prodine series arise from different orientations of this moiety.",
author = "Fries, {David S.} and Portoghese, {Philip S}",
year = "1976",
month = "9",
day = "1",
doi = "10.1021/jm00231a014",
language = "English (US)",
volume = "19",
pages = "1155--1158",
journal = "Journal of Medicinal Chemistry",
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publisher = "American Chemical Society",
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T1 - Stereochemical Studies on Medicinal Agents. 20. Absolute Configuration and Analgetic Potency of α-Promedol Enantiomers. The Role of the C-4 Chiral Center in Conferring Stereoselectivity in Axial- and Equatorial-Phenylprodine Congeners

AU - Fries, David S.

AU - Portoghese, Philip S

PY - 1976/9/1

Y1 - 1976/9/1

N2 - Optical antipodes of the axial phenyl analgetic, α-promedol hydrochloride (3), were prepared and the absolute stereochemistry was determined by relating one of the enantiomers to its γ diastereomer having the 2S,4S,5R configuration. The analgetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, while its enantiomer, (-)-(2S,4R,5R)-3, is inactive at 50 mg/kg. These results are in accord with prior reports which indicate that substitution of a 3- or 5-alkyl group on the pro-4S enantiotopic edge of the piperidine ring leads to enantiomers which have greater potency than those substituted in an identical position on the pro-4R edge. This, coupled with the fact that the torsion angle between the axial phenyl group and piperidine ring in (+)-3 is of the same sign as its equatorial congeners, suggests that the C(3)-C(4)-C(5) moiety and its substituents at C(4) are located in a similar chiral environment on the receptor. In contrast, the C(2)-N-C(6) portion of the axial and equatorial molecules does not bind in the same receptor environment, and it is suggested that different modes of interaction in the prodine series arise from different orientations of this moiety.

AB - Optical antipodes of the axial phenyl analgetic, α-promedol hydrochloride (3), were prepared and the absolute stereochemistry was determined by relating one of the enantiomers to its γ diastereomer having the 2S,4S,5R configuration. The analgetic potency of (+)-(2R,4S,5S)-3 is 20 times that of morphine, while its enantiomer, (-)-(2S,4R,5R)-3, is inactive at 50 mg/kg. These results are in accord with prior reports which indicate that substitution of a 3- or 5-alkyl group on the pro-4S enantiotopic edge of the piperidine ring leads to enantiomers which have greater potency than those substituted in an identical position on the pro-4R edge. This, coupled with the fact that the torsion angle between the axial phenyl group and piperidine ring in (+)-3 is of the same sign as its equatorial congeners, suggests that the C(3)-C(4)-C(5) moiety and its substituents at C(4) are located in a similar chiral environment on the receptor. In contrast, the C(2)-N-C(6) portion of the axial and equatorial molecules does not bind in the same receptor environment, and it is suggested that different modes of interaction in the prodine series arise from different orientations of this moiety.

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