The convulsant and anticonvulsant effects of phencyclidine (PCP) and PCP analogues in the rat.Leccese AP, Marquis KL, Mattia A, Moreton JE.
Behav Brain Res. 1986 Feb;19(2):163-9The pro- and anticonvulsant effects of phencyclidine (1-[1-phenylcyclohexyl]piperidine HCl, PCP), a number of its analogues, and SKF 10047 were investigated in rats. The PCP analogues were compounds produced by substitutions for the phenyl and piperidine rings of PCP and were selected to elucidate the structure-activity relationships existing between PCP and its pro- and/or anticonvulsant effects. All of the compounds, except ketamine, induced convulsions at high (12.8-25.6 mg/kg, i.v.), yet almost always sublethal doses. Ketamine failed to induce convulsions, even at lethal doses (51.2 mg/kg, i.v.). The acute pro- or anticonvulsant actions of PCP were then investigated. Rats were subjected to transorbital electroconvulsive shock subsequent to i.p. injections of saline or 0.625, 2.5, 5.0, 10.0 or 20.0 mg/kg PCP. It was found that PCP induced an acute, dose-dependent anticonvulsant effect. The acute pro- and/or anticonvulsant actions of the remaining compounds were then investigated by administration of electroconvulsive shock subsequent to i.p. injections of saline or one of two doses of each compound. The low and high doses of each compound were selected to be behaviorally equivalent to 2.5 and 10.0 mg/kg PCP i.p., respectively. With one exception, each dose of each drug induced an acute anticonvulsant action, with no difference in efficacy between the compounds tested. However, PCA (produced by substitution of an amine for the piperidine ring of PCP) induced a statistically greater anticonvulsant action at the higher, compared to the lower, dose. In addition, PCA was the only compound to eliminate all motor signs of the electrically induced seizure.
Synthesis, phencyclidine-like pharmacology, and antiischemic potential of meta-substituted 1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines.Thurkauf A, de Costa B, Mattson MV, France CP, Price MT, Olney JW, Woods JH, Jacobson AE, Rice KC.
J Med Chem. 1990 Aug;33(
:2211-5.A series of 1-[1-arylcyclohexyl]-1,2,3,6-tetrahydropyridines were prepared by the reaction between 1-(1-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine (1) and an appropriately substituted Grignard reagent. The resulting compounds were tested for their phencyclidine binding site affinities. Selected compounds were then tested for their ability to produce ketamine appropriate responding in monkeys and/or to show neuroprotective effects in a baby rat hypoxia/ischemia model. While it was found that binding site affinity correlated well with discriminative stimulus effects, it was found to be a poor indicator of neuroprotective efficacy within this series.
Structure-function relationships in the inhibition of synaptosomal dopamine uptake by phencyclidine and analogues: potential correlation with binding site identified with [3H]phencyclidine.Vignon J, Lazdunski M.
Biochem Pharmacol. 1984 Feb 15;33(4):700-2.
Structure-activity relationships of phencyclidine derivatives in rat cerebellum.Pang K, Johnson SW, Maayani S, Freedman R.
Pharmacol Biochem Behav. 1986 Jan;24(1):127-34The depressant effects of phencyclidine [1-(1-phenylcyclohexyl) piperidine, PCP] and three of its analogs (m-amino-PCP, m-nitro-PCP, and PCP-methyliodide) on the spontaneous action potential discharge of cerebellar Purkinje neurons in urethane-anesthetized rats were examined in this study. Both intraperitoneal injection and micro-pressure ejection were employed as routes of drug administration. The relative potency after parenteral administration corresponded closely with previous findings in behavioral test paradigms. PCP and m-amino-PCP were equipotent, m-nitro PCP was less potent than either PCP or m-amino-PCP, and PCP-methyliodide showed almost no activity. After local administration onto neurons, m-amino-PCP was significantly more potent than PCP, while PCP, m-nitro-PCP, and PCP-methyliodide were equipotent. Tritiated PCP, m-nitro PCP, and m-amino PCP have similar distribution and metabolism in cerebellum. PCP-methyliodide, a quaternary ion, does not cross the blood brain barrier. M-nitro PCP is appreciably less ionized at pH 7.4 than PCP or m-amino-PCP and, therefore, may be more easily sequestered into lipids. Differences between PCP and its analogs found in experiments which employ parenteral administration may reflect differences in drug distribution. These differences are minimized when these drugs are administered directly onto neurons via pressure microejection.
Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs.Chaudieu I, Vignon J, Chicheportiche M, Kamenka JM, Trouiller G, Chicheportiche R.
Pharmacol Biochem Behav. 1989 Mar;32(3):699-705.Thirty-seven arylcyclohexylamines including phencyclidine (PCP) and derivatives, N[1-(2-thienyl)cyclohexyl]piperidine (TCP) and derivatives and N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) were assessed for their ability to inhibit [3H]PCP binding and [3H]dopamine ([3H]DA) synaptosomal uptake. Their pharmacological property (ataxia) was measured by means of the rotarod test. A very good correlation was observed between the inhibition of [3H]PCP binding and the [3H]DA uptake only for arylcyclohexylamines bearing an unmodified phenyl group. Conversely the comparison between the inhibition of [3H]PCP binding and the activity in the rotarod test shows a good correlation with arylcyclohexylamines having any aromatic group (phenyl, substituted phenyl and thienyl rings). This study outlined a new compound (BTCP) without ataxic effect, which is one of the more potent inhibitors of the [3H]DA uptake (IC50 = 8 nM) and which seems very specific since it has a low affinity for [3H]PCP receptors (IC50 = 6 microM). These data show that the aromatic group of the compounds leads to molecules that bind differently to the PCP receptor and to the DA uptake complex. They also suggest that the behavioral properties of arylcyclohexylamines revealed by the rotarod test occur essentially as a result of an interaction with the sites labeled with [3H]PCP and that TCP is more selective than PCP itself in this recognition.
Phencyclidine-like effects of tetrahydroisoquinolines and related compounds.Gray NM, Cheng BK, Mick SJ, Lair CM, Contreras PC.
J Med Chem. 1989 Jun;32(6):1242-8.A series of 1,2,3,4-tetrahydroisoquinolines, tetrahydrothieno[2,3-c]pyridines, and related compounds were evaluated for their ability to inhibit binding of [3H]-1-[1-(2-thienyl)piperidine and [3H]-N-allylnormetazocine to phencyclidine (PCP) and sigma receptors, respectively. A representative series of compounds was evaluated in behavioral assays to determine the ability of the compounds to induce PCP-like stereotyped behavior and ataxia. All of the compounds caused stereotyped behavior and ataxia, indicating their agonist actions at the PCP site.
Pharmacokinetic and pharmacodynamic properties of some phencyclidine analogs in rats.Cho AK, Hiramatsu M, Schmitz DA, Nabeshima T, Kameyama T.
Pharmacol Biochem Behav. 1991 Aug;39(4):947-53.The pharmacodynamics and pharmacokinetics of three phencyclidine analogs, differing from phencyclidine (PCP) only in the nature of the amine structure, were determined after intravenous doses of equimolar amounts to rats. The purpose of the study was to assess the role of pharmacokinetics in the in vivo potency of the compounds. The compounds examined were phenylcyclohexyl-pyrrolidine (PCPY), diethylamine (PCDE), ethylamine (PCE), and phencyclohexylamine (PCA). The behavior responses monitored included ataxia and others previously shown to be characteristic of PCP. In contrast to their relative affinities for the MK 801 binding site, the behavioral potencies of PCE, PCDE and PCPY were comparable to PCP. The major discrepancy occurred with PCDE, whose affinity for the NMDA receptor was 1/20th of PCP. The pharmacokinetic studies showed that the discrepancy between in vivo and in vitro activity of PCDE could be partially accounted for by its conversion to PCE, a relatively potent PCP-like agent.
PCP: a review of synthetic methods for forensic clandestine investigation.Allen AC, Robles J, Dovenski W, Calderon S.
Forensic Sci Int. 1993 Oct;61(2-3):85-100.A review of the synthetic routes to phencyclidine (PCP, 1-(1-phenylcyclohexyl)piperidine) available in the open literature is presented. The emphasis herein is directed toward the forensic investigation of clandestine PCP laboratories. Six published synthetic routes to PCP/analogs are discussed. Each method is rated for overall yield, degree of difficulty and potential hazard, in order to assist the forensic chemist in evaluation of a particular clandestine operation. One clandestine recipe is illustrated and discussed.
N-methyl-D-aspartate antagonists and drug discrimination.Koek W.
Pharmacol Biochem Behav. 1999 Oct;64(2):275-81.Excitatory amino acids (EAA), such as glutamate, are thought to be involved in various disorders (e.g., ischemic brain damage, epilepsy, Parkinson's disease), and EAA antagonists have been suggested as potential treatments for these disorders. Phencyclidine (PCP), with produces psychotomimetic effects in humans, has antagonist properties at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors that have been suggested to underlie some of its actions. This suggestion, and concern about possible psychotomimetic activity, has stimulated research aimed at examining to what extent the behavioral profile of other NMDA antagonists resembles that of PCP. Drug discrimination (DD) is prominent among the procedures used to carry out such comparisons. The results of clinical studies with NMDA antagonists provide feedback about the predictive validity of the DD procedures used to characterize their preclinical behavioral profile. Further, DD is used also to examine the ability of compounds to attenuate the discriminative stimulus (DS) effects of PCP-type drugs, and results of such studies have been suggested to provide evidence of antipsychotic potential. Finally, although many instances of intermediate responding in DD can be explained by low efficacy at the receptors that mediate the DS effects of the training drug, certain outcomes produced by PCP-type drugs do not offer valid measures of efficacy, and require more detailed behavioral analyzes.
Effect of lowered lipophilicity on the affinity of PCP analogues for the PCP receptor and the dopamine transporter.Hamon J, Vignon J, Kamenka JM
Eur J Med Chem (1996) 31, 489-495Oxygen and sulphur atoms were introduced in the cyclohexyl and piperidinyl moieties of the basic structures 1-(1-phenyl-cyclohexyl)piperidine (PCP), 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), and 1-[1-(2-benzo
thiophenyl)cyclohexyl]piperidine (BTCP) to lower their global lipophilicity. The compounds obtained were tested comparatively for their affinity for the PCP receptor labelled with [3H]TCP and for the dopamine (DA) transporter labelled with [3H]BTCP. Lowering the global lipophilicity in PCP and TCP series is detrimental to the affinity and selectivity for the PCP receptor. In the BTCP series lowering of the global lipophilicity is less deleterious and may, on the contrary, be a useful way of increasing selectivity for the DA transporter in some instances.
Discriminative stimulus properties of phencyclidine (PCP)-related compounds: correlations with 3H-PCP binding potency measured autoradiographically.Kozlowski MR, Browne RG, Vinick FJ.
Pharmacol Biochem Behav. 1986 Nov;25(5):1051-8. Several PCP analogs, the putative PCP agonist MDP, and the sigma receptor agonists SKF-10,047 and dexoxadrol were tested for their ability to substitute for PCP in animals trained to discriminate PCP from saline. The potencies of these compounds in substituting for PCP in the behavioral task correlated with their abilities to inhibit the specific binding of 3H-PCP to rat hippocampal sections measured autoradiographically, which occurred at a single class of sites with an affinity of 85 nM and a capacity of 2646 fmol/mg protein. In addition to this specific binding, an additional nonspecific but displaceable fraction of total 3H-PCP binding was present. These results suggest that the specific 3H-PCP binding site measured in the hippocampus may be the type of binding site which mediates the behavioral effects of PCP and related compounds. Therefore, measurement of the inhibition of 3H-PCP binding at this site might aid in the search for PCP antagonists.
