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)

6,11-Ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations 8, a novel class of N-methyl-D-aspartate (NMDA) antagonists acting at the phencyclidine site, have been identified. Structure-activity relationship studies around the lead compound 8a led to the identification of 12g (WIN 67870-2), one of the most potent compounds in this series. Compound 12g has a Ki = 1.8 +/- 0.2 nM vs [3H]TCP binding, has 700-fold selectivity for binding to the open state of the NMDA receptor-ionophore, and was devoid of MK-801- and PCP-like behavioral effects in rats. Compound 12g was neuroprotective in cultured mouse cortical neurons and exhibited antiischemic activity in a rat middle cerebral artery occlusion/reperfusion model of focal ischemia.
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PMID:Discovery of 6,11-ethano-12,12-diaryl-6,11-dihydrobenzo[b]quinolizinium cations, a novel class of N-methyl-D-aspartate antagonists. 783 34

NMDA channel blockers are potentially advantageous therapeutic agents for the treatment of ischemia and head trauma, which greatly elevate extracellular glutamate, because they should most effectively inhibit high levels of receptor activation. A novel high affinity TCP site ligand, WIN 63480, does not produce MK-801- or PCP-like behavioral activation at anti-ischemic doses. While WIN 63480, MK-801 and PCP were all observed to be effective blockers of open NMDA channels, WIN 63480 had much less access to closed NMDA channels. This difference may be due to the fact that WIN 63480 is hydrophilic (logD = -4.1) while MK-801 and PCP are lipophilic (logD = +1.8). In vivo, closed channel access may result in a non-competitive profile of antagonism for MK-801 and PCP compared to a more uncompetitive profile for WIN 63480. Release of glutamate, and depolarization, are likely to produce a high level of NMDA receptor activation in ischemic areas compared to normal tissue. Consequently, at anti-ischemic doses, WIN 63480 may produce less inhibition of physiological NMDA-mediated processes in neural systems involved in behavioral regulation than MK-801 or PCP, leading to an improved side effect profile.
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PMID:WIN 63480, a hydrophilic TCP-site ligand, has reduced agonist-independent NMDA ion channel access compared to MK-801 and phencyclidine. 878 57

Although considerable attention has been paid to the relationship between Cannabis use and schizophrenia, there is a significant uncertainty regarding the role of Cannabis consumption in the pathoetiology of the disorder. We investigated the correlation between voluntary cannabinoid consumption and behavioral traits in an animal model of schizophrenia. Male rats were trained to intravenously self-administer the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN; 12.5 microg/kg/infusion) or vehicle; they subsequently received acute or chronic-intermittent intraperitoneal administration of the non-competitive N-methyl-d-aspartate receptor antagonist phencyclidine (PCP; 2.5mg/kg) or saline. We report that WIN self-administration attenuates PCP-induced deficits in (i) prepulse inhibition (PPI) of the acoustic startle reflex, (ii) cognitive skills, and (iii) sociability, suggesting that cannabinoid consumption can ameliorate the schizophrenia-like behavioral alterations caused by PCP. A parallel study performed in animals receiving WIN on a non-voluntary basis (experimenter-given) confirmed an ameliorating effect of cannabinoid administration on the symptoms of schizophrenia induced by PCP.
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PMID:Cannabinoid self-administration attenuates PCP-induced schizophrenia-like symptoms in adult rats. 1985 30