Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.16.2 (PCP)
3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have suggested that a variety of ion channels possess a binding site for ligands such as phencyclidine (PCP), dizocilpine and certain sigma ligands and that some imidazoline compounds can also bind to this site. We have investigated whether interaction with this binding site could account for the ability of imidazolines to stimulate insulin secretion from rat islets. Neither PCP nor dizocilpine shared the insulin secretory activity of the imidazoline efaroxan in rat islets suggesting that they do not have similar actions in the pancreatic B-cell. Further, we were able to define a new antagonist, KU14R (2(2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole), which selectively blocks the insulin secretory response to imidazolines. The results suggest that imidazolines do not stimulate insulin secretion by causing physical blockade of the K(+)-ATP channel in pancreatic B-cells and show that their effects are not reproduced by PCP or sigma receptor ligands.
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PMID:Evidence that the ability of imidazoline compounds to stimulate insulin secretion is not due to interaction with sigma receptors. 912 45

Phencyclidine (PCP) can result in schizophrenia-like behavior. It binds at the PCP site on the NMDA-receptor calcium channel and at the sigma receptor. PCP also induces the heat shock gene hsp7O in retrosplenial cortex neurons. An antipsychotic drug, rimcazole, inhibits PCP hsp7O induction. Rimcazole binds predominantly to sigma-2 sites. It is hypothesized that sigma ligands without antipsychotic properties and with some sigma-2 affinity should partially reverse the effects of rimcazole. (+)-3-PPP, (+)-cyclazocine, and (+)-pentazocine bind predominantly to sigma-I sites. (+)-3-PPP is also a modest sigma-2 ligand. Female Sprague-Dawley rats (200-260 g) were injected intraperitoneally (IP) with (+)-3-PPP (50 mg/kg), rimcazole (60 mg/kg) and, after 5 min, with PCP (40 mg/kg). Brains were sectioned (100 mu m) and presence of the hsp7O gene protein product, HSP7O, was determined immunocytochemically. (+)-3-PPP significantly (0 <0.05) diminished the ability of rimcazole to inhibit PCP hsp7O induction in the retrosplenial cortex. (+)-Cyclazocine (15mg/kg, IP) and (+)-pentazocine (8Omg/kg, IP) given in an analogous manner did not diminish the ability of rimcazole to inhibit PCP hsp7O induction.
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PMID:Effects of sigma ligands on the ability of rimcazole to inhibit PCP hsp70 induction. 913 45

The effect of neuroprotective sigma ligands possessing a range of relative selectivity for sigma and phencyclidine (PCP) binding sites on N-methyl-D-aspartate (NMDA) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated calcium flux was studied in 12-15-day-old primary cultures of rat cortical neurons. In approximately 80% of the neurons tested, NMDA (80 microM) caused a sustained increase in intracellular calcium ([Ca2+]i). With the exception of R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP) (previously shown not to be neuroprotective) all of the sigma ligands studied significantly altered NMDA-induced calcium dynamics. The primary effect of dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF10047, carbetapentane, 1,3-di(2-tolyl) guanidine (DTG), and haloperidol was to shift the NMDA response from a sustained, to either a biphasic or a transient, calcium event. In contrast to NMDA, the primary response observed in 62% of the neurons treated with trans-ACPD (100 microM) was a transient elevation in [Ca2+]i. Here, however, only the highly selective neuroprotective sigma ligands (i.e., those lacking substantial PCP binding affinity) significantly decreased the number of transient responses elicited by trans-ACPD whereas the PCP-related sigma ligands such as dextromethorphan, (+)-SKF10047 and (+)-cyclazocine were ineffective. Unexpectedly, (+)-3-PPP potentiated trans-ACPD activity. These results demonstrating attenuating effects of sigma ligands on NMDA-stimulated neuronal calcium responses agree with earlier studies using glutamate and KCl and identify a sigma receptor modulation of functional NMDA responsiveness. Furthermore, the ability of sigma ligands to attenuate NMDA-, trans-ACPD- and KCl-evoked neuronal calcium dynamics indicates that the receptor mechanisms mediating sigma neuroprotection comprise complex interactions involving ionotropic, metabotropic, and even voltage-gated calcium signaling processes.
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PMID:Neuroprotective sigma ligands attenuate NMDA and trans-ACPD-induced calcium signaling in rat primary neurons. 918 37

Phencyclidine (PCP) is a compound that results in abnormal human behavior and has been proposed as a chemical model for schizophrenia. It was hypothesized that PCP induction of the immediate-early gene, c-fos, should be seen in areas associated with emotional behavior, such as the cortex and limbic system. It was also proposed that PCP may induce c-fos via the sigma receptor. PCP and two sigma ligands, 1,3-di(2-tolyl)guanidine (DTG) and pentazocine, were shown to induce c-fos in similar patterns. The three compounds abundantly induced c-fos in the cingulate, parietal, and piriform cortices and the midline structures of the thalamus and hypothalamus. Neither PCP nor the sigma ligands induced c-fos in the hippocampus. This suggests that PCP binding at NMDA receptors does not result in significant c-fos induction. Rimcazole, a putative sigma2 receptor antagonist, and other sigma ligands have been shown to ameliorate PCP stereotypic behavior. Rimcazole inhibited PCP c-fos induction in the cingulate and parietal cortices and DTG c-fos induction in the cingulate cortex. DTG shows both sigma1 and sigma2 binding affinity. Rimcazole failed to inhibit pentazocine c-fos induction. Pentazocine binds only to sigma1 receptors. This suggests that PCP may produce a significant fraction of its c-fos induction via sigma2 receptors.
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PMID:Phencyclidine (PCP) acts at sigma sites to induce c-fos gene expression. 920 33

The discriminative stimulus properties of compounds that interact with the NMDA receptor complex were investigated in rats trained to discriminate ethanol from saline. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses [fixed ratio 10 (FR10)] for food after ethanol (1 g/kg i.p.; 12% v/v ethanol solution) and saline vehicle injections. Drug effects were assessed by means of generalization and antagonism tests. In the generalization tests, the noncompetitive NMDA antagonists acting at the ion channel dizocilpine, memantine, phencyclidine (PCP) and the sigma1 receptor agonists (+)-pentazocine and (+)-N-allyl-normetazocine (NANM) dose-dependently generalized for ethanol, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonist GYKI 52466, the glycine antagonists L-701,324 and MRZ 2/502, the polyamine site antagonist arcaine and the polyamine site ligand spermidine, did not. Our results show that the noncompetitive NMDA antagonists fully substitute dose-dependently for ethanol in a drug-discrimination task. The ethanol-like discriminative stimulus effects of PCP, pentazocine and NANM, which are also sigma receptor ligands, are likely to be attributed to their activity at NMDA receptors. We therefore assume that some of the acute effects of ethanol are mediated via NMDA receptor antagonism at the PCP binding site.
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PMID:Ethanol and N-methyl-D-aspartate receptor complex interactions: a detailed drug discrimination study in the rat. 948 33

The mechanisms of sigma (sigma) receptor ligands-induced neuroprotective effects are controversial because both sigma receptors and phencyclidine (PCP) binding sites of the N-methyl-D-aspartate (NMDA) receptor channel complex have been reported to contribute to these neuroprotective effects. Thus, to clarify the role of sigma receptor in the neuroprotective effects, we examined the effects of 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503), a novel sigma1 receptor agonist with negligible affinity for the NMDA/PCP receptor channel complex, on the hypoxia/hypoglycemia- and exogenously applied NMDA-induced neurotoxicity in the rat primary neuronal cultures. A selective sigma1 receptor agonist, SA4503, significantly suppressed the hypoxia/hypoglycemia-induced neurotoxicity in the cultures, whereas this agonist failed to inhibit the NMDA-induced neurotoxicity. Similarly, (+)-pentazocine ((+)-PTZ), a prototype sigma1 receptor agonist, inhibited the hypoxia/hypoglycemia-induced neurotoxicity, whilst it did not affect the NMDA-induced toxicity in the cultures. These neuroprotective effects of SA4503 and (+)-PTZ were partially blocked by N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a putative sigma1 receptor antagonist. These results suggest that the sigma1 receptor subtype plays an important role in the sigma receptor ligands-induced neuroprotective effects via the regulation of excitatory amino acids (EAAs) release from the presynaptic sites.
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PMID:Activation of sigma1 receptor subtype leads to neuroprotection in the rat primary neuronal cultures. 959 56

The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane (19F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that 19F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the 18F-labelled analog 18F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tert-butyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl- 5-methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCI. The 18F-MEM was obtained in 22 +/- 7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after i.v. injection of 18F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of 18F-MEM was changed by memantine and by a pharmacological dose of (+)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor antagonist, decreased the binding of 18F-MEM from the brain regions examined, suggesting that binding was also occurring to the sigma recognition sites.
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PMID:Electrophysiological study, biodistribution in mice, and preliminary PET evaluation in a rhesus monkey of 1-amino-3-[18F]fluoromethyl-5-methyl-adamantane (18F-MEM): a potential radioligand for mapping the NMDA-receptor complex. 963 92

1. Electrically induced contractions of the epididymal portion of rat vas deferens were potentiated in concentration-dependent manner (0.1-30 microM) by different sigma and PCP receptor ligands (PCP, TCP, (+)-MK-801, dextromethorphan and (+)-3-PPP); dextrorphan did it in a minor extent. 2. Sigma and PCP receptor ligands also potentiated the effect of noradrenaline, inducing a reduction of the noradrenaline EC50 value in the rat vas deferens. The rank order of potencies was: PCP > TCP > (+)-3-PPP > (+)-MK-801 > dextrorphan > > > dextrometorphan. 3. In contrast, haloperidol (1 microM), a sigma receptor ligand, inhibited both the neurogenic and noradrenaline-induced responses in this tissue. 4. The effect of PCP and sigma receptor ligands on noradrenaline uptake was evaluated. All compounds tested, including haloperidol, inhibited the tritiated noradrenaline incorporation to the tissue. IC50 values were in the micromolar range, between 1.09 microM for dextrophan and 18 microM for dextrometorphan. 5. It is concluded that a direct interaction with the noradrenaline uptake system is involved in the potentiating effect of some sigma and PCP receptor ligands in the epididymal portion of rat vas deferens.
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PMID:Effect of PCP and sigma ligands on both noradrenaline- and electrically-induced contractions and on [3H]-noradrenaline uptake in rat vas deferens. 978 94

In the present study, we clearly showed that the sigma1 receptor subtype did not interact with the induction of stereotyped behaviors in rats. Namely, (+)-N-allylnormetazocine [(+)-SKF-10,047] (5.0, 10.0, and 20.0 mg/kg, SC), a traditional sigma receptor ligand that has affinities for the sigma1 receptor subtype and the N-methyl-D-aspartate (NMDA)/phencyclidine (PCP) receptor channel complex, markedly produced PCP-like stereotyped behaviors, such as head weaving, turning, and backpedaling, in rats. On the contrary, 1-(3,4-dimethoxyphenyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503), a potent and selective sigma1 receptor agonist, did not produce these behaviors. Additionally, PCP-induced stereotyped behaviors were significantly augmented by (+)-SKF-10,047, but not by SA4503. We thus suggest that the induction of PCP-like stereotyped behaviors elicited by (+)-SKF-10,047 closely interacts with NMDA/PCP receptor channel complex but not with the sigma1 receptor subtype.
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PMID:Sigma1 receptor subtype does not interact with stereotyped behaviors in rats. 980 32

Phencyclidine (PCP) binds to many sites in brain, including PCP receptors located within the N-methyl-D-aspartate (NMDA) receptor-operated cation channel and sigma (sigma) receptors. In this study, we compare mechanisms by which PCP, dizocilpine (MK-801), the prototypical sigma receptor agonist (+)-pentazocine, and the proposed endogenous sigma receptor ligand neuropeptide Y regulate potassium (K(+))-stimulated [3H]dopamine release from slices of rat nucleus accumbens. (+)-Pentazocine inhibits K(+)-stimulated [3H]dopamine release, and neuropeptide Y enhances it. Both effects are blocked by sigma(1) and neuropeptide Y receptor antagonists, suggesting possible inverse agonism at a subpopulation of sigma/neuropeptide Y receptors. In contrast, PCP and MK-801 both enhance K(+)-stimulated [3H]dopamine release via sigma(1) and sigma(2) receptor subtypes, as demonstrated by antagonist sensitivity. Regulation of release by both (+)-pentazocine and neuropeptide Y persists in the presence of tetrodotoxin suggests that the sigma/neuropeptide Y receptors mediating the modulation are located presynaptically on dopaminergic nerve terminals, but tetrodotoxin eliminates regulation by PCP and MK-801, suggesting that receptors mediating their effects are located upstream from dopaminergic nerve terminals.
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PMID:Phencyclidine and dizocilpine modulate dopamine release from rat nucleus accumbens via sigma receptors. 1061 64


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