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 acrylat e. Both (+/-) <(cis)under bar> and -(+/-) <(trans)under bar> isomers w ere obtained in pure form and tested pharmacologically for the central analgesic activity: Preliminary results (rat-withdrawal test) reveale d significant but substantially reduced potency of both isomers, the < (trans)under bar> in particular, compared to carfentanil. The computat ional (molecular mechanics) search of the conformational space low ene rgy regions of <(5a)under bar> ((+/-) <(cis)under bar>) and <(5b)under bar> ((+/-) <(trans)under bar> isomers revealed the difference in the ir conformational mobility. Besides being more conformationaly flexibl e trans isomer has unfavorable orientation of the 4-N-phenylpropanamid e group compared to the other active analogs of fentanyl. This is beli eved to be the reason of its reduced potency relative to fentanyl.