Synthesis and Biological Activity of Fluoroalkylamine Derivatives of Narcotic Analgesics

William G. Reifenrath, Edward B. Roche, Walid A. Al-Turk, Howard L. Johnson

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18 Scopus citations

Abstract

N-Ethyl-, N-(2-fluoroethyl)-, N-(2, 2-difluoroethyl)-, and N-(2, 2, 2-trifluoroethyl)-substituted normeperidine (lb-e) and normetazocine (2b-e) derivatives were prepared. The analgesic activities of the compounds were determined in mice. Opiate receptor binding studies, in the presence and absence of sodium ion, were carried out. The antagonist activities of normetazocine derivatives were studied in monkeys. These were further examined in the isolated guinea pig ileum for relative agonist activity. The pKt values were measured; in vivo agonist activity was lost with weakly basic derivatives. For the normetazocine derivatives, opiate receptor binding data were consistent with guinea pig ileum agonist potency and mouse vas deferens antagonist potency but not with in vivo data. Opiate receptor binding was reduced for the less basic normetazocine derivatives. In the normeperidine series, there was no apparent direct relationship between pKt and opiate receptor binding. However, a relationship involving the hydrophobic character of the N-substituent is discussed. The N-(2-fluoroethyl) derivatives in both series were found to cause convulsions in rats at doses of 40-45 mg/kg ip. Elevated serum citrate levels were found in these rats, implicating in vivo oxidative deamination of the N-(fluoroalkyl) substituent to fluoroacetate.

Original languageEnglish (US)
Pages (from-to)985-990
Number of pages6
JournalJournal of Medicinal Chemistry
Volume23
Issue number9
DOIs
StatePublished - Jan 1 1980

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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