3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis
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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 (+/-) lt (cis)under bar gt and -(+/-) lt (trans)under bar gt 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 lt (trans)under bar gt in particular, compared to carfentanil. The computational (molecular mechanics) search of the conformational space low energy regions of lt (5a)under bar gt ((+/-) lt (cis)under bar gt ) and lt (5b)under bar gt ((+/-) lt (trans)under bar gt isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fe...ntanyl. This is believed to be the reason of its reduced potency relative to fentanyl.
Source:Heterocyclic Communications, 1998, 4, 2, 171-179
- Walter De Gruyter Gmbh, Berlin