Paradoxical effects of N-cyanoalkyl upon the activities of several classes of opioids

Article abstract of DOI:10.1021/jm00189a024

The pharmacological effect of the N-(β-cyanoethyl) moiety is dependent on the opioid on which it is substituted. It caused a large increase in antinociceptive potency, in (-)-3-hydroxymorphinan and (-)-normetazocine, as compared with the N-methyl opioid. These cyanoethyl compounds do not substitute for morphine in morphine-dependent monkeys. This moiety also appears to greatly increase the ability of the opiate receptor to differentiate enantiomers. An ca.100 000-fold difference in binding was noted between the epimeric N-(β-cyanoethyl)-3-hydroxymorphinans and the normetazocines. The levo enantiomers have little acute toxicity and showed excellent therapeutic ratios. In contrast, the N-(β-cyanoethyl) moiety on normorphine, norcodeine, and noroxymorphone did not appear to improve their pharmacological properties. Homologous N-cyanoalkyl opioids were less potent antinociceptives.