Synthesis and Biological Activity of Fluoroalkylamine Derivatives of Narcotic Analgesics

Article abstract of DOI:10.1021/jm00183a005

N-Ethyl-, N-(2-fluoroethyl)-, N-(2,2-difluoroethyl)-, and N-(2,2,2-trifluoroethyl)-substituted normeperidine (1b-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 agonist activity.These pK_a values were measured in vivo agonist activity was lost with the weakly bas ic 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 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 pK_a 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.