Paradoxical effects of N-cyanoalkyl substituents upon the activities of several classes of opioids.
The pharmacological effect of the N-(beta-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-(beta-cyanoethyl)-3-hydroxymorphinans and the normetazocines. The levo enantiomers have little acute toxicity and showed excellent therapeutic ratios. In contrast, the N-(beta-cyanoethyl) moiety on normorphine, norcodeine, and noroxymorphone did not appear to improve their pharmacological properties. Homologous N-cyanoalkyl opioids were less potent antinociceptives.
D000478:Alkylation; D000700:Analgesics; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D000882:Haplorhini; D007928:Lethal Dose 50; D008253:Macaca mulatta; D051379:Mice; D009294:Narcotics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects; D013329:Structure-Activity Relationship
D000700:Analgesics; D009294:Narcotics; D011957:Receptors, Opioid