morphinans and normetazocine

The inhibitory potency of opioids belonging to different structural categories on electric eel and rat brain acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) was investigated. The phenylazepine meptazinol, the pyrrolo-[2,3-b]-indole derivative eseroline and the benzomorphan normetazocine were the most potent inhibitors of AChE among the compounds tested. These were followed by (-)-metazocine, N-allylnorcyclazocine, 3-(1,3-dimethyl-3-pyrrodinyl)-phenol, levallorphan, levorphanol and pentazocine. The opioids which inhibited horse serum BuChE were in order of potency: meptazinol, methadone, profadol, levallorphan and 1,2,3-trimethyl-3-(3-hydroxyphenyl)-piperidine. The results of this work appear consistent with the fact that the anticholinesterase activity of the opioids is not confined to specific structural categories, although conformationally constrained molecules, like those of morphinans, benzomorphans or pyrrolo-[2,3-b]-indoles, appear to favour affinity for AChE, whereas highly flexible molecules, like those of acyclic opioids, inhibit BuChE in a rather selective way. In all cases, the inhibitory action of opioids markedly differed from that of carbamates or organophosphorous compounds, in that it was time-independent and immediately reversible on dilution. In general the anticholinesterase action of opioids does not seem to influence appreciably the pharmacological properties of the drugs since it is evidenced at drug doses higher than those which are analgesic. However, in the case of mixed agonist/antagonist opioids with rather weak analgesic activity, the enzyme inhibition caused by the levels of circulating drugs can be so marked as to exert also a cholinergic component of action.

Topics: Acetylcholinesterase; Analgesics; Analgesics, Opioid; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cyclazocine; Dose-Response Relationship, Drug; Electrophorus; Horses; Models, Molecular; Morphinans; Morphine; Narcotics; Rats

Topics: Analgesics, Opioid; Animals; Benzomorphans; Cyclazocine; Female; Lethal Dose 50; Male; Mice; Morphinans; Morphine; Narcotics; Structure-Activity Relationship

The reaction of N-2,4,5-tribenzyloxyphenyl)ethyl methanesulfonate, prepared in a seven-step sequence, with normetazocine followed by hydrogenolysis of the benzyloxy-protecting groups, gave N-(2,4,5-trihydroxyphenethyl)normetazocine. This compound was prepared to study the effect of a narcotic analgesic containing a functional group which could be activated in situ to a moiety potentially capable of reacting irreversibly with the narcotic receptor. This 6-hydroxydopamin derivative of normetazocine did not prove to be a useful affinity label. Its low toxicity could indicate the necessity for the formation of an aminochrome system for the expression of toxicity by 6-hydroxydopamine.

Topics: Adenylyl Cyclases; Analgesics, Opioid; Animals; Benzomorphans; Brain; Cyclazocine; Depression, Chemical; In Vitro Techniques; Male; Mice; Morphinans; Neoplasms, Experimental; Neuroblastoma; Norepinephrine; Protein Binding; Rats; Receptors, Opioid