Phencyclidine analogs and precursors: rotarod and lethal dose studies in the mouse
Vaupel, D.B.; McCoun, D.; Cone, E.J.
Journal of Pharmacology and Experimental Therapeutics 230(1): 20-27
1984
ISSN/ISBN: 0022-3565 PMID: 6747825 Document Number: 226007
A series of phencyclidine (PCP) related analogs, carbonitrile synthetic precursors and 2 monohydroxylated metabolites were compared pharmacologically in mice for their ability to produce ataxia using the rotaroid method and toxicologically for their acute 4-h 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 0.05-2.15 .times. PCP and durations of action ranged from 18-65 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. 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-phenycyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the 3 precursors. These studies demonstrate that the PCP analogs, but not the metabolites or precursors, produce similar effects. [Implications with respect to human drug abuse are presented.].