Synthesis,structural, conformational and pharmacological study of new fentanyl derivatives of the camphidine system

A series of N-phenethyl-8-β-amidocamphidines 4a-f (3-phenethyl-8-β-(N-arylamido)-3-azabicyclo-[3.2.1]octane) has been designed, synthesized and stereochemically characterized as semirigid analogous of the 4-anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. In deuteriochloroform and deuteriobenzene solution, compounds 4a-f display the same preferred conformation. The cyclopentane and piperidine rings adopt an envelope and distorted chair conformation respectively flattened at N-3, with the N and C-8 substituents in equatorial and axial positions with respect to the piperidine ring. In vivo pharmacological testing demonstrated that compounds 4a-f were inactive in the analgesic test, with the exception of compound 4f which showed an ED₅₀ of 250 mg/kg p.o.