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)

Acute cerebral ischemia and reperfusion injury of rabbits was produced by permanently occluding the vertebral arteries and temporarily clamping the common carotid arteries for 30 min. Phencyclidine [1-(phenylcyclohexyl)piperidine, PCP] 40-80 micrograms.kg-1 icv 30 min before ischemia significantly attenuated the decrease of the total power of electroencephalogram (EEG) within 30 min of ischemia and improved the recovery of brain electric activity following reperfusion. PCP 20-80 micrograms.kg-1 dose-dependently suppressed the creatine kinase (CK) release during cerebral ischemia and reperfusion, and PCP 40-80 micrograms.kg-1 reduced brain ischemic damage. These improvements indicated that PCP has protective effects on acute cerebral ischemia and reperfusion injury.
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PMID:Neuroprotective effects of phencyclidine on acute cerebral ischemia and reperfusion injury of rabbits. 144 2

A novel series of octahydrophenanthrenamines and their heterocyclic analogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds were evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [3H]TCP from crude rat brain synaptic membranes. A wide range of affinities were observed, with the most potent analogs possessing IC50's equivalent to that of the reference agent MK-801 (3, dizocilpine). NMDA antagonist activity was demonstrated by prevention of glutamate-induced accumulation of [45Ca2+] in cultured rat cortical neurons. Selected compounds were also studied in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the phenanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt >> NC5H10; (b) for the B-ring substitution, X = CH2 > S > O; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C rings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phenanthrenamine system identified an additional hydrogen bonding interaction that substantially increased receptor affinity; (f) spiro analogues (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Molecules from this series were useful for refining a pharmacophore model consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putative receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by approximately 5-10-fold than their corresponding (S)-(-)-enantiomers with respect to their affinity for the PCP site, their ability to prevent accumulation of [45Ca2+] in cultured neuronal cells, and their protection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and the dose that produced ataxia in mice, except in the case of the thiaphenanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the treatment of cerebral ischemia or other neurodegenerative disorders.
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PMID:Synthesis and pharmacological evaluation of 4a-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-D-aspartate receptor complex. 833 37

There has been considerable interest in the potential of N-methyl-D-aspartate (NMDA) receptor antagonists in the treatment of a diverse group of neurological disorders including cerebral ischemia and neurodegeneration. The amino acids L-glutamate and L-aspartate have been shown to possibly mediate excitatory synaptic transmission in the central nervous system (CNS) via selective excitatory amino acid receptors. Competitive and noncompetitive antagonists acting at the NMDA receptors have been shown to possess relevant activity. However, NMDA antagonists can produce a variety of adverse neurobehavioral effects in both animals and humans. These adverse events are particularly pronounced with NMDA antagonists (phencyclidine (PCP), ketamine, and MK-801) that have dissociative anesthetic properties and block NMDA receptor-mediated responses by binding to the cation channel of the NMDA receptor complex. When a new pharmaceutical product demonstrates structural similarity and/or a similar pharmacological profile with a known drug of abuse, the characterization of its abuse potential is needed by the FDA for scientific review. The abuse liability assessment is based upon an evaluation of data on the chemistry, pharmacology (preclinical and clinical), pharmacokinetics, and pharmacodynamic profiles of the drug, and the adverse events/effects reported in clinical trials. The evaluation of the drug's abuse potential is determined relative to pharmacologically similar drugs. This includes determination of the drug's receptor binding efficacy, preclinical pharmacology, reinforcing efficacy, discriminative stimulus effects, dependence-producing potential, pharmacokinetics, and assessment of the clinical efficacy-safety database relative to abuse and clinical abuse liability studies. It has been well established that high-affinity noncompetitive NMDA antagonists have reinforcing efficacy and can serve as discriminative stimuli in operant procedures. In a variety of species in drug discrimination studies, each antagonist is capable of generalizing to the others, and it is believed that these effects may be mediated through the NMDA blockade. The generalization of each substance for another suggests production of common subjective effects in humans.
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PMID:Abuse liability assessment of neuroprotectants. 1066 57

Elucidation of the metabolism and pharmacology of 1,2,3-triazolines (TRs) led to the identification of the triazoline pharmacophore and the evolution of the aminoalkylpyridines (AAPs). The AAPs have no activity in the scMet test but are highly effective in the MES seizure test by the oral route. The AAPs bind to the sigma(1) receptor with low affinity, but high selectivity. They impair Glu release to the same extent as the triazolines and afforded a high degree of protection in the kindled rat. They show no affinity for the NMDA/PCP receptor sites; thus the toxic side effects of NMDA antagonists are absent in the sigma selective AAPs. Variations of the heterocyclic unit, the alkyl chain and the amino group in the AAP leads, indicated that the 4-pyridyl substituent along with a methyl (alkyl) group, and a 4-C1, 3-C1 or 3,4-C1(2) substitution on the N-phenyl group, afforded the most active compounds. Amino group modification by acylation did not improve activity. The hydrazone compounds were the most active. Although the AAPs are very effective in the MES and the kindling models of epilepsy, they showed only low to moderate activity in protecting neuronal cells in stroke-induced cerebral ischemia. In the case of the TR compounds, even the least effective TR afforded 47% protection from neuronal injury. It is not known at this point, whether activity in both the MES and scMet tests, which would imply a role for both Glu and GABA, is a prerequisite for antiischemic activity.
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PMID:Aminoalkylpyridines (AAPs), triazoline metabolite analogues, as anticonvulsants highly effective in the MES test. 1287 Oct 88