Stereochemical Studies on Medicinal Agents. 14. Relative Stereochemistries and Analgetic Potencies of Diastereomeric 3-Allyl and 3-Propyl Derivatives of 1-Methyl-4-phenyl-4-propionoxypiperidine

Kevin H. Bell, Philip S Portoghese

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22 Citations (Scopus)

Abstract

An improved synthesis of diastereomeric (±)-3-allyl-1-methyl-4-propionoxypiperidine (2a, b) is described, and the 3-propyl analogs 3a, b have been prepared. The relative stereochemistries of 2a, b have been deduced from chemical and nmr studies and are opposite to that proposed originally by others. The analgetic potency of 2a is 15 times greater than that of morphine and 116 times greater than 2b. The propyl analog 3a is much less potent (1/24) than 2a, indicating that the double bond of the 3-allyl group is responsible for the increased activity. The fact that the rank orders of potencies for the allyl (2a > 2b) and propyl (3a > 3b) diasteromers are opposite to that found in the prodines (1b > 1a) suggests that the mode of interaction of 2b and 3b with analgetic receptors is different from that of β-prodine (1b). A stereochemically positioned hydrophobic pocket of limited size on the receptor has been proposed to rationalize this reversal of stereoselectivity. Certain aspects of the role of conformational isomerism in the action of these analgetics are discussed.

Original languageEnglish (US)
Pages (from-to)203-205
Number of pages3
JournalJournal of Medicinal Chemistry
Volume16
Issue number3
DOIs
StatePublished - Mar 1 1973

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Alphaprodine
Isomerism
Morphine
4-propionyloxy-4-phenyl-N-methylpiperidine

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abstract = "An improved synthesis of diastereomeric (±)-3-allyl-1-methyl-4-propionoxypiperidine (2a, b) is described, and the 3-propyl analogs 3a, b have been prepared. The relative stereochemistries of 2a, b have been deduced from chemical and nmr studies and are opposite to that proposed originally by others. The analgetic potency of 2a is 15 times greater than that of morphine and 116 times greater than 2b. The propyl analog 3a is much less potent (1/24) than 2a, indicating that the double bond of the 3-allyl group is responsible for the increased activity. The fact that the rank orders of potencies for the allyl (2a > 2b) and propyl (3a > 3b) diasteromers are opposite to that found in the prodines (1b > 1a) suggests that the mode of interaction of 2b and 3b with analgetic receptors is different from that of β-prodine (1b). A stereochemically positioned hydrophobic pocket of limited size on the receptor has been proposed to rationalize this reversal of stereoselectivity. Certain aspects of the role of conformational isomerism in the action of these analgetics are discussed.",
author = "Bell, {Kevin H.} and Portoghese, {Philip S}",
year = "1973",
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T1 - Stereochemical Studies on Medicinal Agents. 14. Relative Stereochemistries and Analgetic Potencies of Diastereomeric 3-Allyl and 3-Propyl Derivatives of 1-Methyl-4-phenyl-4-propionoxypiperidine

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N2 - An improved synthesis of diastereomeric (±)-3-allyl-1-methyl-4-propionoxypiperidine (2a, b) is described, and the 3-propyl analogs 3a, b have been prepared. The relative stereochemistries of 2a, b have been deduced from chemical and nmr studies and are opposite to that proposed originally by others. The analgetic potency of 2a is 15 times greater than that of morphine and 116 times greater than 2b. The propyl analog 3a is much less potent (1/24) than 2a, indicating that the double bond of the 3-allyl group is responsible for the increased activity. The fact that the rank orders of potencies for the allyl (2a > 2b) and propyl (3a > 3b) diasteromers are opposite to that found in the prodines (1b > 1a) suggests that the mode of interaction of 2b and 3b with analgetic receptors is different from that of β-prodine (1b). A stereochemically positioned hydrophobic pocket of limited size on the receptor has been proposed to rationalize this reversal of stereoselectivity. Certain aspects of the role of conformational isomerism in the action of these analgetics are discussed.

AB - An improved synthesis of diastereomeric (±)-3-allyl-1-methyl-4-propionoxypiperidine (2a, b) is described, and the 3-propyl analogs 3a, b have been prepared. The relative stereochemistries of 2a, b have been deduced from chemical and nmr studies and are opposite to that proposed originally by others. The analgetic potency of 2a is 15 times greater than that of morphine and 116 times greater than 2b. The propyl analog 3a is much less potent (1/24) than 2a, indicating that the double bond of the 3-allyl group is responsible for the increased activity. The fact that the rank orders of potencies for the allyl (2a > 2b) and propyl (3a > 3b) diasteromers are opposite to that found in the prodines (1b > 1a) suggests that the mode of interaction of 2b and 3b with analgetic receptors is different from that of β-prodine (1b). A stereochemically positioned hydrophobic pocket of limited size on the receptor has been proposed to rationalize this reversal of stereoselectivity. Certain aspects of the role of conformational isomerism in the action of these analgetics are discussed.

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