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)

Metaphit, an isothiocyanate analog of phencyclidine (PCP), increased the basal release of radioactivity (outflow) from perfused rat striatal slices preloaded with [3H]dopamine above levels observed with the dopamine uptake blocker nomifensin. Preperfusing the slices with metaphit, followed by its removal, attenuated the amphetamine- or dopamine-induced outflow. In slices prepared from reserpine-pretreated rats, the metaphit (100 microM)-induced outflow was reduced to that observed with 10 microM nomifensin, suggesting a vesicular releasing effect of metaphit in addition to dopamine uptake blockade. Electrically induced overflow of radioactivity from normal slices was stimulated by nomifensin and PCP, and by metaphit at 3 microM; it was unaffected by metaphit at 10 and 25 microM, and inhibited by higher concentrations of metaphit. Evidence that the latter effect is due to blockade of voltage-dependent sodium channels is as follows. First, metaphit, as did PCP, inhibited the binding of [3H]batrachotoxinin A 20-alpha benzoate to rat striatal synaptoneurosomes by increasing its dissociation rate; the effect of PCP, but not that of metaphit, was reversible by washing. Second, metaphit, as did PCP, inhibited veratridine (5 microM)-induced influx of [14C]guanidinium ion into synaptoneurosomes. Third, metaphit inhibited overflow of radioactivity from [3H]dopamine-preloaded slices induced by 2.5 microM veratridine, as did the sodium channel blocker tetrodotoxin.
J Pharmacol Exp Ther 1991 Dec
PMID:Effect of metaphit on dopaminergic neurotransmission in rat striatal slices: involvement of the dopamine transporter and voltage-dependent sodium channel. 166 74

Membrane preparations of rat hearts displayed specific binding activity for the prototypic sigma (sigma) receptor ligand, 1,3-di(2-[5-3H]tolyl) guanidine [( 3H]DTG), but not for the phencyclidine (PCP) receptor ligand, [3H]MK-801. Scatchard plot analysis of [3H]DTG binding revealed the presence of one high affinity saturable binding site with a KD of 8.7 nM and a Bmax of 100 pmol/g protein. The drug specificity profile of the receptor correlated with that of the sigma receptor with the following order of potency: DTG greater than haloperidol greater than (-)-pentazocine greater than (-)-butaclamol greater than (+)-butaclamol greater than (-) SKF-10047 greater than (+)pentazocine greater than PCP greater than TCP greater than MK-801 greater than (+)SKF-10047. [3H]DTG binding was sensitive to the Ca2+ channel blocker, verapamil (Ki 202 nM) but not to the K+ channel blocker, 4-aminopyridine. The reverse stereoselectivity of [3H]DTG binding for (-)-SKF-10047 and (-)-pentazocine (Ki of 1289 and 140 nM as compared with 17,582 and 2190 nM for (+)-SKF-10047 and (+)-pentazocine, respectively) indicated that the heart contains sigma receptors with characteristics of the sigma 2 subtype.
Eur J Pharmacol 1991 Dec 17
PMID:Interaction of 1,3-di(2-[5-3H]tolyl) guanidine with sigma 2 binding sites in rat heart membrane preparations. 166 96

The specific binding of [3H]TCP and [3H](+)3-PPP, radioligands which respectively label PCP-NMDA and sigma binding sites was measured in tissue homogenates prepared from dissected areas of control and schizophrenic postmortem brains. [3H]TCP binding was bilaterally increased in orbital frontal cortex (Brodmann area 11) of schizophrenic brains. This finding may be due to an increased glutamatergic innervation of orbital frontal cortex since it parallels our findings of increased [3H]kainate and [3H]D-aspartate binding in this area. In contrast, [3H](+)3-PPP binding was reduced in each of the four brain regions examined. The reductions were greatest in brains from the schizophrenic subjects receiving neuroleptics at the time of death. Neuroleptics remaining in the brains of these subjects may compete in vitro with [3H](+)3-PPP for binding to the sigma site.
Schizophr Res 1991 Dec
PMID:Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Effects of disease process and neuroleptic medication. 168 83

Experimental evidence suggests that neuronal pharmacologic sites termed sigma (sigma) may be related, but not identical to PCP sites in the ion channel linked to NMDA excitatory receptors. These receptors may play a role in schizophreniform psychoses, and clinical trials of putative sigma-ligands have begun. Because of this, and because of the relationship of sigma-ligands to NMDA receptors, we studied the effect of the most selective presently available sigma-ligand on ischaemic neuronal death throughout the rat brain after transient forebrain ischaemia. Ventricular delivery of DTG at 0.5 mumol/h via an osmotic minipump was chosen to allow continuous access of the drug to brain tissue, control animals receiving artificial CSF. After one week survival, selective neuronal necrosis was reduced in the hippocampus, but not in the neocortex or striatum, contrasting with our previous findings in this model with pure NMDA antagonists. The results indicate that ischaemic neuronal necrosis in the hippocampus may be mitigated by sigma-agonists, possibly via an interaction with NMDA receptors.
Neurol Res 1991 Dec
PMID:Intraventricular infusion of the selective sigma-agonist 1,3-di-ortho-tolylguanidine (DTG) mitigates ischaemic brain damage in the hippocampus. 168 37

[3H]ryanodine binding to and Ca2+ release from microsomal fractions derived from canine cerebrum (CBR) and cerebellum (CBL) were investigated. High-affinity ryanodine binding sites were detected in both cerebrum and cerebellum microsomes [CBR: maximal binding capacity (Bmax) = 446 fmol/mg protein, dissociation constant (Kd) = 9 nM, Hill coefficient (n) = 0.95; CBL: Bmax = 650, Kd = 12, n = 1.8]. Ryanodine binding in both fractions was increased by millimolar concentrations of ATP [or its nonhydrolyzable analogue beta, gamma-methyleneadenosine 5'-triphosphate (AMP-PCP)] and micromolar concentrations of Ca2+ but was decreased by micromolar concentrations of ruthenium red, similar to that found in sarcoplasmic reticulum (SR) of striated muscle. The addition of caffeine or the sudden elevation of extravesicular Ca2+ induced a rapid La(3+)-sensitive Ca2+ release from both CBR and CBL microsomal fractions with rate constants of approximately 100 s-1, as determined by stopped-flow photometry of the Ca2+ indicator arsenazo III. The release of Ca2+ was activated by either millimolar ATP or AMP-PCP, blocked by micromolar concentrations of La3+, and significantly inhibited by 50 microM ryanodine. Mg2+ and ruthenium red in millimolar and micromolar concentrations, respectively, caused only a slight inhibition of Ca2+ release. These results indicate that rapid Ca2+ release occurs from caffeine-, Ca2+- and ryanodine-sensitive Ca2+ stores in both CBR and CBL microsomal fractions.
Am J Physiol 1991 Dec
PMID:Caffeine- and ryanodine-sensitive Ca2+ stores of canine cerebrum and cerebellum neurons. 172 42

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.
Science 1991 Dec 06
PMID:NMDA antagonist neurotoxicity: mechanism and prevention. 183 99

The possible role of protein phosphorylation in modulation of [3H]glibenclamide binding to the sulphonylurea receptor, a putative ATP-sensitive K-channel, was investigated in the cloned pancreatic beta-cell line, HIT T15. Diazoxide, an opener of ATP-sensitive K-channels, increased HIT cell 86Rb-efflux, inhibited insulin secretion and decreased non-competitively [3H]glibenclamide binding to intact HIT cells. ATP-depletion reduced the [3H]glibenclamide binding activity of intact cells but did not change diazoxide-insensitive binding. Although diazoxide alone did not change the binding of [3H]glibenclamide to HIT cell membranes, the simultaneous presence of MgATP revealed an inhibition of [3H]glibenclamide binding by diazoxide. This effect of MgATP was reproduced by MgATP gamma S, but not by MgADP, MgAMP-PNP or MgAMP-PCP. These findings suggest that protein phosphorylation may be involved in the response of ATP-sensitive K-channels to diazoxide.
Biochim Biophys Acta 1991 Dec 03
PMID:Possible involvement of protein phosphorylation in the regulation of the sulphonylurea receptor of a pancreatic beta-cell line, HIT T15. 183 60

SKF 10,047 (N-allylnormetazocine) was found to be neuroprotective against glutamate-induced excitotoxicity in our model system of energy-stressed neurons which rapidly succumb to glutamate via N-methyl-D-aspartate (NMDA) receptor-mediated events. The 50% protective concentration (PC50) of the (+) and (-) enantiomers was 3.3 microM and 9 microM, respectively, against the toxic action of 100 microM glutamate. Protection by SKF 10,047 seemed to be mediated by the lower-affinity phencyclidine (PCP) binding site rather than the higher-affinity sigma-site since the potent sigma-ligand (+)-3-(3-hydroxyphenyl-N-1-propyl)piperidine [+)-3-PPP) did not protect at concentrations up to 2 mM. A reversed stereoselectivity was apparent for neuroprotection since (-)-3-PPP was weakly protective with a PC50 of 1.5 mM. These data suggest that energy-stressed rat cerebellar granule cells are a useful model for identifying neuroprotective agents, as shown by SKF 10,047.
Neurosci Lett 1990 Dec 11
PMID:Excitatory amino acid neurotoxicity at the N-methyl-D-aspartate receptor in cultured neurons: protection by SKF 10,047. 198 87

Thirty-nine male patients (average age 50.8 years +/- 8.4 years) with a large anterior myocardial infarction (average 45.6 days +/- 10.5 days ago) and with moderate to severe left-ventricular dysfunction (RNVA EF less than 50%) participated in the study. The patients were randomly assigned to either a training group or to a control group. They were also subdivided into training/control groups (EF less than 30% and EF = 30-50%). The training program consisted of three to four sessions per day, 5 days a week, at an intensity of up to 1 W/kg body wt. (approximately 4-5 METS). The following evaluations were recorded prior to and following the 4-week training program: relative heart volume (x-ray), echocardiographic data (enddiastolic diameter, ES-distance, and shortening fraction), and exercise stress test (work capacity, heart rate). Filling pressures, cardiac outpout, and stroke volume index were calculated from right-heart catheterization (Swan-Ganz) at rest and during exercise. Results indicate that there were no significant changes in relative heart volume, end-diastolic volume, ES-distance, resting heart rate, PCP at rest, and ejection fraction during exercise as a result of the training program. Shortening fraction showed a tendency to improve (not significant). Work capacity increased by 15 W (p less than 0.05) in the training group and by 28 W (1.5 METS, p less than 0.05) in the EF less than 30% training-group as compared with the control group. Cardiac output at rest decreased by 10% (p less than 0.05). Stroke-volume index increased in the EF greater than 30% training-group, while heart rate was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
Z Kardiol 1990 Dec
PMID:[Four-week training of patients with large anterior wall infarct: comparison with a randomized untrained control group]. 208 63

The postnatal development of the three receptor binding sites that constitute the N-methyl-D-aspartate (NMDA) receptor channel/complex was examined in six hippocampal regions of rats using quantitative receptor autoradiography. NMDA-sensitive [3H]-glutamate binding, strychnine-insensitive [3H]glycine binding, and [3H]N-(1-[2-thienyl]cyclohexyl)-3,4-piperidine [( 3H]TCP) binding were measured to examine the ontogeny of NMDA recognition sites, glycine modulatory sites, and PCP receptors, respectively. NMDA-sensitive [3H]glutamate binding transiently exceeded adult levels by 50 to 120% in all regions examined, with peak densities generally occurring between postnatal days (PND) 10 and 28. Stratum radiatum CA1 binding increased slowly from 49 to 61% of the adult value between PND 1 and 7, after which, binding rapidly rose to 151% of adult values at PND 14, remained elevated through PND 28, and then decreased to adult levels. The ontogenic profile of NMDA recognition site binding was similar in other hippocampal regions, although the initial age of maximal binding and the period of stabilization varied. The ontogenic profiles of glycine modulatory site binding and PCP receptor binding were very similar to each other. Development was delayed, however, with respect to NMDA recognition site binding. The rapid development of binding observed between PND 7 and 14 with NMDA receptors in stratum radiatum CA1 was contrasted by a much slower increase in glycine and PCP receptor binding. Furthermore, maximal glycine and PCP receptor binding densities were not reached until PND 28 and were lower than NMDA recognition site binding densities. The observed developmental patterns of binding to each of the receptor components of the NMDA receptor channel/complex are consistent with postnatal changes in cytoarchitecture, synaptogenesis, afferent lamination, and functional development of the hippocampus. However, the relative overexpression of NMDA recognition sites with respect to glycine and PCP receptors between PND 7 and 21 suggests that there is differential expression of these binding sites during development.
Exp Neurol 1990 Dec
PMID:Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus. 217 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>