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)

Electrophilic and photoactivated agents have proven to be useful as receptor-selective irreversible probes. These compounds are generally derivatives of selected ligands that may be chemically modified in such a way as to retain high receptor affinity and selectivity while permitting covalent bonding to the receptor protein. The receptor systems described in this chapter are associated with a variety of classes of abused drugs. These irreversible agents are allowing the isolation and purification of these drug receptors to improve our understanding of their physiological and pharmacological properties and to aid us in better design of agents with therapeutic value without abuse or physical dependence liability. In the opioid field, beta-FNA and SUPERFIT have been successfully used to elucidate structure and function of the mu-, kappa-, and delta-receptors, respectively. Recently, the delta- and kappa-subtype selective irreversible ligands naltrindol and UPHIT have been introduced for receptor subtype studies that are designed to further clarify the physiological function of these sites. The PCP recognition site on the NMDA receptor complex and the sigma receptors have been characterized in part by the use of irreversible agents. These receptors, although sharing similar pharmacological properties, are clearly different systems and the irreversible agents described will allow their further characterization. The central-type benzodiazepine receptors have been labeled with irreversible agents; and, now, receptor subsites that differentially recognize beta-carbolines and benzodiazepines have been discovered through studies using a beta-carboline photoaffinity probe. The associated chloride ionophore has been studied with electrophilic irreversible ligands, as well as the pharmacologically distinct peripheral-type benzodiazepine receptors. Physiological function of the latter receptor system has been implicated through the photoaffinity ligand PK 14105, which is highly selective for these sites. Receptor subtype selective irreversible ligands also have been prepared for both the dopamine and sertonin receptors systems in hopes of clarifying their physiological roles in the CNS. It is clear that more selective irreversible compounds with higher affinity will continue to be in demand for further receptor characterization. In addition, radioligands with higher specific activity will continue to be important for molecular weight determination of receptor proteins and autoradiographic studies key to neuroanatomical localization of these sites.
 ...
PMID:Irreversible ligands as probes for drug receptors. 166 79

Glutamate evoked contractions of the longitudinal muscle/myenteric plexus (LMMP) preparation by an action at N-methyl-D-aspartate (NMDA) receptors. Other agonists at the NMDA recognition site, but not quisquilate or kainate, also contracted the LMMP, and glutamate-evoked contractions were competitively inhibited by selective NMDA receptor antagonists. Glutamate-evoked contractions were noncompetitively inhibited by MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine moleate], phencyclidine (PCP) and other compounds that bind to the PCP receptor, which is a binding site on the NMDA channel complex. Their potencies for this effect were highly correlated with their affinities for the PCP receptor. Glycine significantly shifted the glutamate concentration-response curve to the left. Glycine site antagonists caused a glycine-sensitive, noncompetitive inhibition of glutamate-evoked contractions, and their potencies for this effect were highly correlated with their affinities for the glycine binding site of the NMDA channel complex. Mg++ and Zn++ also noncompetitively inhibited glutamate-evoked contractions. The modulatory effects of glycine, Mg++, Zn++ and PCP receptor ligands were specific to glutamate-evoked contractions. MK-801 was highly selective for inhibition of glutamate-evoked contractions; MK-801 also inhibited nicotinic responses at a 500-fold lower potency. Two novel compounds are described that bind to the PCP receptor with high affinity and selectively inhibit glutamate-evoked contractions in the LMMP.
 ...
PMID:N-methyl-D-aspartate receptor-mediated contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation: modulation by phencyclidine and glycine receptors. 167 35

It is no longer tenable to attribute all the antipsychotic action of antipsychotic drugs to dopamine (DA) D2 receptor blockade and subsequent development of depolarization inactivation of the mesolimbic or mesocortical DA neurons. The chief evidence for this position is that clozapine (CLOZ) does not differ from typical antipsychotic drugs in these regards but is more effective than typical neuroleptic drugs. The mechanism of action of atypical antipsychotic drugs related to CLOZ may involve reduction of dopaminergic activity in the mesolimbic system by a variety of mechanisms, including D1 and D2 receptor blockade. Relatively higher affinity for the serotonin (5HT)2 receptor than for the D2 receptor may also be important to the action of CLOZ-like compounds. Enhanced DA release in the mesocortical system may be relevant to the effectiveness of these agents in treating negative symptoms. Several other classes of new agents alter the dopaminergic system by means of alternative mechanisms. Partial DA agonists may modulate DA neurotransmission more adequately than pure antagonists by producing a mix of direct agonist and antagonistic effects. DA autoreceptor agonists and 5HT3 antagonists appear to act by diminishing the release of DA from some, but not all, DA neurons. Substituted benzamides are "pure" D2 antagonists with some in vivo selectivity for limbic D2 over striatal D2 receptors. Highly selective D1 antagonists have been proposed to produce equivalent antipsychotic activity and fewer extrapyramidal symptoms than D2 antagonists. Antagonists of the recently identified D3 receptors are being sought. Excessive stimulation of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, leading to neurotoxicity or diminished activation of this receptor, is the target of novel approaches to treating schizophrenia. Phencyclidine (PCP) antagonists that would activate the NMDA receptor and sigma receptor antagonists are of interest as antipsychotic agents. Therapeutic strategies for treating schizophrenia, schizophrenia-related disorders, and other psychoses will likely be genuinely diverse in the next decade.
 ...
PMID:The mechanism of action of novel antipsychotic drugs. 167 53

Glycine potentiates N-methyl-D-aspartate (NMDA) receptor-mediated responses via its interaction with a strychnine-insensitive glycine recognition site. We have previously shown that the potent glycine receptor antagonist 7-chlorokynurenic acid (7Cl-KYN) dose-dependently inhibits [3H]MK-801 binding to the PCP receptor and that this effect is reversed by glycine. [3H]MK-801 binding to the PCP receptor within the NMDA receptor-gated ion channel is a measure of channel activation. Association of PCP receptor ligands is biexponential with the fast component of binding serving as a marker of activated NMDA channels. In the present study we utilize 7Cl-KYN as a probe of the kinetic mechanism of the glycine effect upon NMDA receptor functioning. In the presence of L-glutamate, incubation with 7Cl-KYN completely abolished the fast component of [3H]MK-801 association in 4 out of 5 experiments. In the fifth experiment where the fast component was detected, it accounted for less than half of that seen in the presence of L-glutamate alone. 7Cl-KYN-induced inhibition of the fast component of [3H]MK-801 association was reversed by the addition of glycine. Since the fast component represents ligand binding to the PCP receptor via the open NMDA channel, selective reduction of this component by 7Cl-KYN indicates that glycine receptor antagonists reduce the probability of channel opening, and also that the selective reduction in the component of [3H]MK-801 binding that manifests fast kinetics can serve as a marker for glycine antagonists.
 ...
PMID:Kinetic mechanisms of glycine requirement for N-methyl-D-aspartate channel activation. 168 9

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.
 ...
PMID:Neurochemical and behavioral aspects of lamotrigine. 168 39

Polyamines such as spermidine potentiate activation of the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. The goal of the present study was to investigate interactions between the putative polyamine binding site and previously described sites for glutamate and glycine. Binding of the high-potency PCP receptor ligand [3H]MK-801 to well-washed rat brain membranes was used as an in vitro probe of NMDA receptor activation. Spermidine concentration-response studies were performed in the absence and presence of both glutamate and glycine, with and without D-(-)-2-amino-5-phosphonovaleric acid (D(-)-AP-5) or 7-chlorokynurenic acid (7Cl-KYN). Incubation in the presence of spermidine alone induced a 20.4-fold increase in [3H]MK-801 binding with an EC50 value of 13.3 microM. The mean concentration of spermidine which induced maximal stimulation of binding was 130 microM (n = 10, S.E.M. = 24.66, range = 25-250 microM). Glutamate (10 microM) decreased the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding to 3.4 microM. Glycine (10 microM) did not significantly alter either maximum spermidine-induced [3H]MK-801 binding or the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding. Incubation in the presence of the specific glutamate antagonist D(-)AP-5 attenuated [3H]MK-801 binding in a glutamate-reversible fashion. The competitive glycine antagonist 7Cl-KYN decreased maximum spermidine-induced [3H]MK-801 binding in a glycine-reversible fashion. In addition, 7Cl-KYN increased the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding while D(-)AP-5 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Polyamine effects upon N-methyl-D-aspartate receptor functioning: differential alteration by glutamate and glycine site antagonists. 168 87

Because of its apparent effectiveness in detecting non-benzodiazepine anxiolytic agents, a recently introduced conflict procedure in pigeons was used to evaluate possible anti-punishment activity of various N-methyl-d-aspartate (NMDA) antagonists. Punished responding was significantly increased by competitive NMDA antagonists (CPP, CGS 19755), but not by noncompetitive NMDA antagonists acting at either the ion channel (PCP, ketamine, MK-801), the glycine site (kynurenic acid, 7-chlorokynurenic acid, ACPC), or the polyamine site (ifenprodil) of the NMDA receptor complex; the proposed glutamate antagonist, riluzole, was also ineffective.
 ...
PMID:Use of a conflict procedure in pigeons to characterize anxiolytic drug activity: evaluation of N-methyl-D-aspartate antagonists. 171 31

Modulation of spinal systems activated by N-methyl-D-aspartate (NMDA) and substance P administered IT have been an area of interest in several laboratories. In the present investigations, behavior induced by the excitatory amino acid kainic acid, but not quisqualate, is demonstrated to be modulated in a manner similar to that previously observed for NMDA. Biting, scratching and licking behavior was induced by IT injections of excitatory amino acids or substance P in mice. Behavior induced by kainic acid (IT) injection was inhibited in a dose-dependent manner by coadministration of morphine (ICV), norepinephrine (IT), N-ethyl carboxamidoadenosine (NECA) (IT) and agonists interacting at PCP receptors (IT). Kainic acid and NMDA differed, however, in that a dopaminergic agonist, apomorphine, inhibited kainic acid-, but not NMDA-induced behavior and a selective NMDA receptor antagonist inhibits NMDA-, but not kainic acid-induced behavior. Behavior induced by quisqualate (IT) was not inhibited by any treatment and may have nonspecific actions in this type of assay. Our observations support independent spinal sites of action for behavior induced by kainic acid and NMDA, but several similarities were observed in the modulation of spinal systems activated by these agents.
 ...
PMID:Descending systems activated by morphine (ICV) inhibit kainic acid (IT)-induced behavior. 171 10

Pretreatment with metaphit (1-[1-(3-isothiocyanotophenyl)cyclohexyl]piperidine), a putative irreversible antagonist of phencyclidine (PCP) receptors, did not antagonize PCP-induced passive avoidance deficit in rats, and did not decrease [3H]MK-801 (5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate) binding to PCP recognition sites coupled to NMDA receptors. The effectiveness of the metaphit treatment was evidenced by the occurrence of audiogenic seizures. These results suggest that previously reported antagonism in vivo actions of PCP by metaphit, is mediated by sites not involved in PCP-induced passive avoidance deficit, and not related to the NMDA receptor complex in brain structures studied (striatum, hippocampus, and cortex).
 ...
PMID:Metaphit fails to antagonize PCP-induced passive avoidance deficit. 182 88

Neuropeptide Y (NPY) and peptide YY (PYY) are known to bind with high affinity to sigma (sigma) and phencyclidine (PCP) binding sites in rat brain. The functional significance of these results was assessed by testing both peptides in an in vitro bioassay system used for studying the N-methyl-D-aspartate (NMDA) receptor and consisting of rat hippocampal slices preloaded with [3H]noradrenaline (NA) and maintained under superfusion. The addition of NMDA in the superfusion medium induced an efflux of [3H]NA from the slices and the presence of NPY and PYY produced an enhancement of the stimulating effect. These results suggest that NPY and PYY could have a modulatory role at the NMDA receptor complex through an interaction with the sigma and/or PCP receptor.
 ...
PMID:N-methyl-D-aspartate receptor complex modulation by neuropeptide Y and peptide YY in rat hippocampus in vitro. 182 14


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