Different fentanyl derivatives have been developed by the legitimate pharmaceutical industry by adding various substituents to the basic molecule in order to modify potency (Table 1). This approach has been mimicked by chemists in clandestine laboratories to produce illicit NPF derivatives. Depending on the position of the substituents, some of the resulting molecules may exist as enantiomers e.g. the isomers of 3-methylfentanyl, which have differing analgesic potencies depending on which enantiomer is used. Van Bever et al. (1974) reported that the introduction of a methyl group (-CH3) into the 3 position of the piperidine ring, increases analgesic potency. The trans isomer was slightly more active than fentanyl, but its corresponding cis form was eight times more active. They found that activity of the cis isomer resided in one enantiomer, namely cis(+) 3-methylfentanyl which was16 times more potent than fentanyl, whereas the cis(-) form was 120 times less potent (see non-pharmaceutical fentanyls below).
