A series of
phencyclidine (PCP) related analogs, carbonitrile synthetic precursors and two monohydroxylated metabolites were compared pharmacologically in mice for their ability to produce
ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. The slope of the PCP dose-ataxic response curve was steeper than those of
diazepam,
pentobarbital,
morphine and
ketocyclazocine but not the slope of the sigma agonist,
N-allylnormetazocine curve. Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP.
Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 X PCP and durations of action ranged from 18 to 65 min.
N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-
piperidine and 1-[1-(2-thienyl)-cyclohexyl]-
pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl
morpholines and
4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the
piperidine or aromatic ring effected changes only in potency.
Seizures and
respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded
seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-
piperidine, 1-[1-(2-thienyl)-cyclohexyl]-
piperidine,
N-ethyl-1-phenylcyclohexylamine and
ketamine and the smallest were for
1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite
4-phenyl-4-piperidinocyclohexanol and the three precursors.(ABSTRACT TRUNCATED AT 250 WORDS)