Psychotomimetics as anticholinergic agents. I. 1-Cyclohexylpiperidine derivatives: anticholinesterase activity and antagonistic activity to acetylcholine

Phencyclidine (sernyl^®, 1-[(1 -phenylcyclohexyl)piperidinel]) and ten of its derivatives, known for their psychotomimetic activity, are potent competitive inhibitors of butyry-lcholinesterase and acetylcholinesterase. The drugs also protect the enzyme against inactivation by an organophosphate (sarin), presumably by their direct interaction with the active site. In addition to the acetylcholine-like structural factors identifiable in these molecules, the cyclohexyl moiety is considered necessary for the interaction. The drugs are also competitive antagonists of acetylcholine in perfused organs (guinea-pig ileum, frog rectus abdominis) and in the eye of three mammals. This peripheral activity is three orders of magnitudes less potent than that of atropine. Antiacetylcholine activity in the central nervous system was studied through the antidotal effect of THA (tacrine), before and after injection of the drugs. The correlation between the anticholinesterase activity and the CNS activity as well as the structural relation of the drugs to agonists and antagonists of the cholinergic system is discussed