Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC(50) values of 0.022 and 2.5 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D(1) and D(2) dopamine receptors, and 5-HT(1A) and 5-HT(2A) serotonin receptors in membranes prepared from rat brain or to cloned 5-HT(6) and 5-HT(7) receptors. At 10 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT(7) serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg i.p.) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg i.p.). Both NFPS and Org 24461 (1-10 mg/kg i.p.) reversed PCP-induced changes in EEG power spectra in conscious rats. These data support the view that GlyT1 inhibitors may have potential importance in treatment of negative symptoms of schizophrenia.
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PMID:The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study. 1266 95

Phencyclidine (PCP), an antagonist at the N-methyl-D-aspartate subtype of ionotropic glutamatergic receptors, decreases gamma-aminobutyric acid (GABA)ergic inhibition, suggesting that changes in GABAergic receptor function underlie behavioral and cognitive deficits resulting from repeated administration of PCP. To test this hypothesis, male Sprague-Dawley rats treated with PCP (4.5 mg/kg, intraperitoneal, twice a day for 7 consecutive days) or saline were tested in behavioral and cognitive tasks 7 days after injections. The PCP group showed increased amphetamine (1.5 mg/kg)-stimulated locomotor activity, and exhibited a greater number of errors in the double Y-maze memory task, when compared with controls. Subchronic PCP treatment increased [H]muscimol-binding sites and decreased affinity for [H]muscimol binding in frontal cortex, hippocampus, and striatum in comparison with controls. There were no changes in the expression of glutamic acid decarboxylase or the GABA membrane transporter protein. These data show that subchronic PCP administration induces an impaired performance of a previously learned task and an enhanced response to amphetamine in the rat. The observed changes in GABAA receptors in the rat brain are consistent with the notion that alterations in GABAergic receptor function contribute to the behavioral and cognitive impairments associated with repeated exposure to PCP.
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PMID:Subchronic phencyclidine in rats: alterations in locomotor activity, maze performance, and GABA(A) receptor binding. 1994 21