STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF PHENCYCLIDINE DERIVATIVES IN RATS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 228  (1) , 147-153
Abstract
Phencyclidine (PCP) [an anesthetic and analgesic with abuse liability], a semirigid molecule containing a cyclohexane ring with vicinally attached aromatic and piperidine rings, produces characteristic discriminative stimulus properties and pupillary miosis in rats. The effectiveness of a series of aromatic and nitrogen substituted analogs of PCP [3NH2-PCP, 1-[1-(m-aminophenyl)cyclohexyl]piperidine HCl; 3F-PCP, 1-[1-(m-fluorophenyl)cyclohexyl]piperidine HCl; PMCP, 1-[1-(1-phenylmethyl)cyclohexyl]piperidine HCl; PECP, 1-(1-(2-phenylethyl)cyclohexyl]piperidine HCl; PPCP, 1-[1-(3-phenylpropyl)cyclohexyl]piperidine HCl; 1NCP, 1-[1-(1-napthyl)cyclohexyl]piperidine HCl; 2NCP, 1-[1-(2-napthyl)cyclohexyl]piperidine HCl; 3NO2-PCP, 1-[1-(n-nitrophenyl)cyclohexyl]piperidine HCl; 3PCHP, 1-(1-phenylcyclohexyl)-3-hydroxypiperidine HCl; 3MePCP, 1-(1-phenylcyclohexyl)-3-methylpiperidine HCl; 4MePCP, 1-(1-phenylcyclohexyl)-4-methylpiperidine HCl; PCDMA, N,N-dimethyl-1-phenylcyclohexylamine HCl; NIPPCA, N-(isopropyl)-1-phenylcyclohexylamine HCl; NSBPCA, N-(s-butyl)-1-phenylcyclohexylamine HCl; PCHHMI, 1-(1-phenylcyclohexyl)hexamethyleneimine HCl] in producing PCP-like discriminative stimuli and changes in pupil diameter was determined in rats trained to discriminate between saline and 3.0 mg/kg of PCP. Dexoxadrol and its optical isomer levoxadrol were evaluated for purposes of comparison. Analogs in which the electron-density of the aromatic ring was increased (3NH2-PCP) or only slightly reduced (3F-PCP) retained PCP-like activity. A loss of PCP-like activity occurred with analogs in which the electron-density of the aromatic ring was greatly reduced (3NO2-PCP) or extended to a larger system (1NCP and 2NCP). PCP-like activity was abolished in analogs in which the distance between the aromatic ring and the remainder of the molecule was systematically increased by 1, 2 or 3 methylene units. Substitutions on the N atom altered the potency, but not the efficacy, of such analogs. Dexoxadrol produced PCP-like activity whereas its optical enantiomer levoxadrol was devoid of such activity. A drug receptor surface with multiple domains or subsites which recognize regions of structural overlap among the phencyclidines, dioxolanes and psychotomimetic benzomorphan derivatives, is suggested.

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