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)

Compounds that produce depolarization of nociceptive neurons in the dorsal horn of the spinal cord also elicit a rather specific kind of caudally directed biting, licking, and/or scratching behavior when they are injected intrathecally in mice. We sought to use this elicited grooming behavior as a test for compounds that might inhibit the neurons excited by the excitatory agents. All three neurokinins--substance P, neurokinin A (substance K), neurokinin B (neuromedin K)--and excitatory amino acids active at N-methyl-D-aspartate (NMDA) or quisqualate receptors produce similar behaviors, which last for 1 minute after i.t. injection. Our data indicate that mu opioid agonists or alpha adrenergic agonists block both neurokinin-elicited behavior and EAA-elicited behavior; delta opioid agonists block only neurokinin-elicited behavior; and PCP/sigma "opioid" agonists block only EAA-elicited behavior. Somatostatin and serotonin produce qualitatively different behaviors by themselves and, when administered with neurokinins, partially block neurokinin-elicited behavior.
 ...
PMID:Pharmacological studies of grooming and scratching behavior elicited by spinal substance P and excitatory amino acids. 245 61

Drug discrimination studies have proven useful for comparing and contrasting the behavioral effects of site-selective N-methyl-D-aspartate (NMDA) antagonists. This study examined the effects of competitive and non-competitive NMDA antagonists in squirrel monkeys trained to discriminate 1 mg/kg D-CPPene [D-3-(2-carboxypiperazine-4-yl)-1- propenyl-1-phosphonic acid; SDZ EAA 494] from vehicle in a two-lever drug discrimination procedure. Results show that D-CPPene and several other competitive NMDA antagonists (NPC 17742, CGS 19755, and CGP 37849) completely substituted for D-CPPene in a dose-dependent manner. In contrast, phencyclidine (PCP) and ketamine produced only partial substitution at doses that severely suppressed response rates. These results are consistent with results of earlier studies with rats and monkeys showing differences in the discriminative stimulus effects of competitive and PCP-like non-competitive NMDA antagonists. The data support the predictions (1) that D-CPPene and the other competitive NMDA antagonists tested would have similar subjective effects in humans and (2) that some differences would be found in the subjective effects of competitive NMDA antagonists and PCP-like non-competitive antagonists.
 ...
PMID:Effects of competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists in squirrel monkeys trained to discriminate D-CPPene (SDZ EAA 494) from vehicle. 789 15

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.
 ...
PMID:The pharmacology of SDZ EAA 494, a competitive NMDA antagonist. 789 35

The studies described demonstrate that rat brain mRNA directs the synthesis of at least four types of functional EAA receptors in the Xenopus oocyte system, whereas in this system NCB-20 cell mRNA directs the synthesis of only the NMDA type of EAA receptor. The NMDA channel expressed in the oocyte, using either rat brain mRNA or NCB-20 cell mRNA, exhibits the pharmacologic properties of the neuronal receptor, including the functional association with the PCP receptor located within the NMDA-gated channel. The demonstration that mRNA isolated from NCB-20 cells lacking functional NMDA-activated channels, but bearing PCP binding sites, can encode functional NMDA-activated channels in the oocyte indicates some defect or regulating step in posttranslational processing or insertion of the receptors into the plasma membrane in the cell of origin. This is the only cell line known to (1) have PCP receptors that appear to be associated with NMDA receptors and (2) provide a homogeneous, self-replicating population of cells that can be manipulated genetically and by changing the extracellular environment. Consequently, the NCB-20 cell line will be useful for the study of the NMDA receptor and its expression.
 ...
PMID:Molecular biology of PCP and NMDA receptors. 823 12

Drug discrimination studies in rats and monkeys with competitive N-methyl-D-aspartate. (NMDA) antagonists as training drugs have shown that these drugs typically cross-substitute for each other, whereas phencyclidine (PCP)-like NMDA channel blockers produce partial, if any, substitution. In the present study, rats and squirrel monkeys were trained to discriminate the competitive NMDA antagonist, NPC 17742, from vehicle in a two-lever drug discrimination procedure for food reinforcement. The competitive NMDA antagonists, NPC 12626, SDZ EAA 494 (D-CPPene), and MDL 100,453 fully substituted for NPC 17742 in monkeys or in rats. The relative potencies of these compounds were similar across species. Open channel blockers, PCP and dizocilpine, and the tricyclic antidepressant and low affinity PCP-site ligand, desipramine, produced minimal responding on the NPC 17742-associated lever in rats or monkeys. The glycine-site modulators, (+)-HA-966, ACEA 1021 and milacemide, and the polyamine/NR2B-selective antagonist, eliprodil, also failed to substitute fully for NPC 17742 in rats and monkeys. These data complement and extend results of previous studies which have shown a lack of PCP-like discriminative stimulus effects of these non-competitive NMDA antagonists by further showing that they also do not share discriminative stimulus effects with those produced by many competitive NMDA antagonists. These observations would support a prediction that differences in side-effect profiles should emerge among types of NMDA antagonists.
 ...
PMID:Discriminative stimulus effects of site-selective N-methyl-D-aspartate antagonists in NPC 17742-trained rats and squirrel monkeys. 929 16

We have previously reported that a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), produces stereotyped behaviors and hyperlocomotion in amygdala kindled rats at doses which do not induce such phencyclidine (PCP)-like behaviors in nonkindled rats, indicating that kindling predisposes rats to such adverse effects of competitive NMDA receptor antagonists. From these data we predicted that epileptic patients may exhibit a hypersensitivity to PCP-like adverse effects of competitive NMDA receptor antagonists, which was subsequently confirmed in a clinical trial with D-CPPene (SDZ EAA-494; 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonate). For further exploration of the functional alterations in NMDA receptor responsiveness produced by kindling, we studied whether the enhanced susceptibility of amygdala-kindled rats to PCP-like adverse effects of CGP 37849 is also observed with D-CPPene. Furthermore, we determined whether the enhanced susceptibility of kindled rats to such adverse effects occurs only after relatively short intervals following the last seizure, as used in our previous study, or is a more permanent phenomenon. For this purpose, we compared adverse effects in kindled rats not only with naive (non-implanted) controls, as done in our previous study, but used electrode-implanted nonkindled rats as an additional control to assess the possible bias of mere electrode-implantation. In addition, we studied whether the enhanced susceptibility to NMDA receptor antagonists of electrically kindled rats is also present in chemically kindled animals. In some experiments, the PCP-like uncompetitive NMDA receptor antagonist MK-801 (dizocilpine) was included for comparison. In amygdala kindled rats, D-CPPene produced significantly more stereotyped behaviors than in electrode-implanted or naive nonkindled controls. The enhanced sensitivity of electrically kindled rats to PCP-like stereotypies induced by D-CPPene was observed both 7 and 180 days after the last kindled seizure, indicating a long-lasting if not permanent hypersensitivity to these adverse effects. In addition, more intense circling was observed in amygdala kindled rats, whereas hyperlocomotion only tended to be more intense after D-CPPene in kindled rats. These alterations in D-CPPene-induced behaviors were not observed after chemical kindling with pentylenetetrazole, but D-CPPene induced significantly less hypothermia in chemically kindled rats both 7 and 70 days after the last seizure. The data demonstrate that kindling produces long-lasting alterations in some adverse effects of D-CPPene, substantiating that epileptogenesis as initiated by kindling renders the brain more susceptible to PCP-like behavioral side effects of competitive NMDA receptor antagonists.
 ...
PMID:Electrical but not chemical kindling increases sensitivity to some phencyclidine-like behavioral effects induced by the competitive NMDA receptor antagonist D-CPPene in rats. 972 48

Antagonists at the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor are purported to have detrimental effects on cognitive processes. In order to examine the site selectivity of these effects, phencycline (PCP), dizocilpine, and memantine (PCP-site antagonists), SDZEAA 494 and NPC17742 (competitive NMDA antagonists), ACEA 1021 (glycine-site antagonist), and eliprodil (NR2B-selective polyamine-site selective antagonist) were tested in rats performing a delayed nonmatch-to-sample task. Dizocilpine, PCP and memantine significantly decreased accuracy and discriminability, particularly during brief delay trials. In contrast, the competitive NMDA antagonists, SDZ EAA 494 and NPC 17742, did not affect accuracy or discriminability at any delay. Similarly, ACEA 1021, and eliprodil did not alter behavioral indices in a manner suggesting compromise in information processing at any delay even at doses that decreased the total number of trials completed. These data support previous findings that the effects of NMDA antagonists on accuracy are site-selective, with PCP-site antagonists producing the greatest disruption. Further, while not conclusive, the results are consistent with the hypothesis that NMDA receptor-mediated neurotransmission may be important at early stages of information processing, although further research is necessary to confirm these latter observations.
 ...
PMID:NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats. 1174 96