Stereochemical Studies on Medicinal Agents. VI. Bicyclic Bases. Synthesis and Pharmacology of Epimeric Bridged Analogs of Meperidine, 2-Methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptane

Philip S Portoghese, A. A. Mikhail, H. J. Kupferberg

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Epimeric 2-methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptanes were elaborated from N,O,O-tritosylhydroxyprolinol, and the stereochemistry was determined from physicochemical studies. The benzoquinoneinduced writhing test indicated the endo-phenyl epimer to be twice as potent as meperidine and six times more potent than the exo isomer. In terms of brain concentrations, however, the endo-exo potency ratio is 3.7. Evidence is presented which quantitatively relates difference in brain levels between the epimers to their partition coefficients. The large difference in geometry between the exo and endo epimers suggests that their comparable activities are due to differing modes of interaction with analgetic receptors.

Original languageEnglish (US)
Pages (from-to)219-225
Number of pages7
JournalJournal of Medicinal Chemistry
Volume11
Issue number2
DOIs
StatePublished - Mar 1 1968

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Heptanes
Meperidine
Pharmacology
Brain

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title = "Stereochemical Studies on Medicinal Agents. VI. Bicyclic Bases. Synthesis and Pharmacology of Epimeric Bridged Analogs of Meperidine, 2-Methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptane",
abstract = "Epimeric 2-methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptanes were elaborated from N,O,O-tritosylhydroxyprolinol, and the stereochemistry was determined from physicochemical studies. The benzoquinoneinduced writhing test indicated the endo-phenyl epimer to be twice as potent as meperidine and six times more potent than the exo isomer. In terms of brain concentrations, however, the endo-exo potency ratio is 3.7. Evidence is presented which quantitatively relates difference in brain levels between the epimers to their partition coefficients. The large difference in geometry between the exo and endo epimers suggests that their comparable activities are due to differing modes of interaction with analgetic receptors.",
author = "Portoghese, {Philip S} and Mikhail, {A. A.} and Kupferberg, {H. J.}",
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T1 - Stereochemical Studies on Medicinal Agents. VI. Bicyclic Bases. Synthesis and Pharmacology of Epimeric Bridged Analogs of Meperidine, 2-Methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptane

AU - Portoghese, Philip S

AU - Mikhail, A. A.

AU - Kupferberg, H. J.

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Y1 - 1968/3/1

N2 - Epimeric 2-methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptanes were elaborated from N,O,O-tritosylhydroxyprolinol, and the stereochemistry was determined from physicochemical studies. The benzoquinoneinduced writhing test indicated the endo-phenyl epimer to be twice as potent as meperidine and six times more potent than the exo isomer. In terms of brain concentrations, however, the endo-exo potency ratio is 3.7. Evidence is presented which quantitatively relates difference in brain levels between the epimers to their partition coefficients. The large difference in geometry between the exo and endo epimers suggests that their comparable activities are due to differing modes of interaction with analgetic receptors.

AB - Epimeric 2-methyl-5-phenyl-5-carbethoxy-2-azabicyclo[2.2.1]heptanes were elaborated from N,O,O-tritosylhydroxyprolinol, and the stereochemistry was determined from physicochemical studies. The benzoquinoneinduced writhing test indicated the endo-phenyl epimer to be twice as potent as meperidine and six times more potent than the exo isomer. In terms of brain concentrations, however, the endo-exo potency ratio is 3.7. Evidence is presented which quantitatively relates difference in brain levels between the epimers to their partition coefficients. The large difference in geometry between the exo and endo epimers suggests that their comparable activities are due to differing modes of interaction with analgetic receptors.

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