Stereochemical Studies on Medicinal Agents. 21. Investigation of the Role of Conformational Factors in the Action of Diphenylpropylamines. Synthesis and analgetic Potency of 5-Methylmethadone Diastereomers

James G. Henkel, Eric P. Berg, Philip S Portoghese

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Abstract

The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (±)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.

Original languageEnglish (US)
Pages (from-to)1308-1314
Number of pages7
JournalJournal of Medicinal Chemistry
Volume19
Issue number11
DOIs
StatePublished - Nov 1 1976

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Methadone
Stereoisomerism
Hydrogen
5-methylmethadone
isomethadone

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title = "Stereochemical Studies on Medicinal Agents. 21. Investigation of the Role of Conformational Factors in the Action of Diphenylpropylamines. Synthesis and analgetic Potency of 5-Methylmethadone Diastereomers",
abstract = "The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (±)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.",
author = "Henkel, {James G.} and Berg, {Eric P.} and Portoghese, {Philip S}",
year = "1976",
month = "11",
day = "1",
doi = "10.1021/jm00233a011",
language = "English (US)",
volume = "19",
pages = "1308--1314",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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T1 - Stereochemical Studies on Medicinal Agents. 21. Investigation of the Role of Conformational Factors in the Action of Diphenylpropylamines. Synthesis and analgetic Potency of 5-Methylmethadone Diastereomers

AU - Henkel, James G.

AU - Berg, Eric P.

AU - Portoghese, Philip S

PY - 1976/11/1

Y1 - 1976/11/1

N2 - The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (±)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.

AB - The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (±)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.

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