3-CARBOMETHOXY FENTANYL: SYNTHESIS, PHARMACOLOGY AND CONFORMATIONAL ANALYSIS

The synthesis of a novel analogue of fentanyl, 3-carbomethoxy fentanyl or "iso-carfentanil" has been accomplished in five steps, by simple and efficient route, starting from phenethyl amine and methyl acrylate. Both (±) cis and (t) trans isomers were obtained in pure form and tested pharmacologically for the central analgesic activity. Preliminary results (rat-withdrawal test) revealed significant but substantially reduced potency of both isomers, the trans in particular, compared to carfentanil. The computational (molecular mechanics) search of the conformational space low energy regions of 5a ((±) cis) and 5b ((±) frans) isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible trans isomer has unfavorable orientation of the 4-/V-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.