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)

Three non-competitive antagonists (MK-801, TCP, PCP) and one competitive antagonist (CPP) of N-methyl-D-aspartate (NMDA) receptors, were compared for their ability to antagonize neurotoxic actions of NMDA injected into the brains of 7-day-old rats. Unilateral intracerebral injection of NMDA (25 nmol/0.5 microliters) into the corpus striatum of pups consistently produced severe confluent neuronal necrosis in the striatum extending into the dorsal hippocampus and overlying neocortex. The distribution of damage corresponded to the topography of NMDA type glutamate receptors in the vulnerable regions. With this lesion in developing brain, the weight of the injected hemisphere 5 days later can be used as a quantitative measure of brain injury. Intraperitoneal administration of MK-801 (0.02-42.0 mumol/kg), TCP (3.5-54.0 mumol/kg), PCP (1.0-41.0 mumol/kg), and CPP (1.0-60.0 mumol/kg) 15 min after NMDA injection had prominent dose-dependent neuroprotective effects. MK-801 was 14 times more potent than other compounds tested and the 50% protective dose (PD50, that dose which reduced damage by 50% relative to untreated NMDA-injected controls) was 0.63 mumol/kg. Corresponding values for CPP, PCP, and TCP were 8.84, 10.85, and 24.05 mumol/kg respectively. The lowest dose of MK-801 that provided significant protection was 0.2 mumol/kg (0.04 mg/kg, 37.9 +/- 4.6% protection). Four mumol/kg (0.8 mg/kg) of MK-801 completely protected against NMDA-mediated damage. The study provides the first direct in vivo comparison of the neuroprotective abilities of these compounds. Systemic administrations of MK-801, TCP, PCP, and CPP all limit NMDA-induced neuronal injury in this model. The susceptibility of the immature brain to the neurotoxicity of NMDA provides a sensitive, reproducible, and quantitative in vivo system for comparing the effectiveness of drugs with protective actions against excitotoxic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl-D-aspartate induced neurotoxicity in an in vivo perinatal rat model. 266 94

Beef heart mitochondrial ATPase (F1) catalyzes the hydrolysis of the ATP analog adenyl-5-yl imidodiphosphate (AMP-PNP). The reaction products are inorganic phosphate and adenyl-5-yl phosphoramidate (AMP-PN) as determined by HPLC analysis. The hydrolysis occurs in both the presence and absence of added divalent metal ions and is stimulated by potassium. The kinetic properties of the hydrolytic reaction depend markedly on the identity of the added divalent metal. GMP-PNP and AMP-CPP are also hydrolyzed, while AMP-PCP is not. Adenyl-5-yl phosphoramidate is a potent effect of beef heart mitochondrial ATPase activity. Based on these data, a reinterpretation of work based on the assumption that AMP-PNP is not hydrolyzed is presented.
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PMID:Hydrolysis of adenyl-5-yl imidodiphosphate by beef heart mitochondrial ATPase. 286 12

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.
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PMID:Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. 289 25

1. Adult female Culex pipiens and Culiseta inornata have purinergic receptors that respond to extracellular ADP and related compounds. Stimulation of these receptors caused ingestion of artificial diets. Addition of bicarbonate to the saline solvent enhanced the phagostimulatory effect. Saline-bicarbonate was as effective a solvent as blood plasma for Cx. pipiens, and was used in the dose-effect determinations. Ranking of the potencies was: ADP greater than AMP-PNP greater than ATP = AMP greater than AMP-PCP much greater than 2'dAMP greater than 2'dADP greater than 2'dATP. At 1 mM concentration, ITP, GTP, CTP, UTP, c-AMP, 2'AMP, 3'AMP, DPG, or GSH + glucose caused fewer than 50% of the insects to gorge, as did 2'3'dd-ATP, A tetra P, and AMP-CPP at 100 microM. 2. The potency ranking for Cu. inornata was: ADP greater than AMP-PNP greater than ATP greater than AMP-PCP much greater than AMP much greater than AMP-S. The concentrations required to produce the ED50 response (inducing 50% of the test insects to gorge) were much higher than those required for Cx. pipiens; however, saline, not saline-bicarbonate, was used as the solvent. With the exception of the very low potency of AMP for Cu. inornata, the ADP potency index values for the other chemicals tested on both species are similar.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Purinergic reception by culicine mosquitoes. 290 19

Rats were trained to discriminate phencyclidine (PCP) from saline at doses of 2 and 4 mg/kg, using a two-lever food reinforced operant technique. +/- N-allylnormetazocine (+/- SKF 10047), +5-methyl-10,11-dihydro-5H-dibenzo[A,D]cyclohepten-5,10-imine MK 801), 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and ifenprodil, which have been shown to antagonise the effects of N-methyl-D-aspartate (NMDA), were tested for their ability to give rise to PCP-appropriate responding. In rats trained at both doses of PCP, +/- SKF 10047 (2-12 mg/kg) and MK 801 (0.0125-0.2 mg/kg) produced dose-related responding on the lever associated with PCP injection. The relative potency of these two compounds was the same in the two groups of animals, but their absolute potencies to produce a PCP-like discriminative stimulus were dependent on the training dose of PCP. In contrast, neither the competitive NMDA antagonist CPP (4-20 mg/kg) nor the non-competitive antagonist ifenprodil (2-12 mg/kg) produced PCP-appropriate responding and ifenprodil (4 mg/kg) neither potentiated nor antagonised PCP. These findings are discussed in the light of the hypothesis that the behavioural effects of PCP are mediated via a reduction of neurotransmission at the NMDA-subtype of glutamate receptors.
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PMID:Is the discriminative stimulus produced by phencyclidine due to an interaction with N-methyl-D-aspartate receptors? 290 45

A soluble ATP/Mg2-dependent proteolytic system from rabbit cardiac muscle has been identified (m ca. 310 kDa) and purified ca. 9-fold. This enzyme which splits the substrate [3H]globin and 125I-bovine serum albumin (125I-BSA) has many similarities to the ATP-dependent proteolytic enzyme system from reticulocytes which utilizes ubiquitin: 1) The specific activities in reticulocyte lysates and cardiac muscle extracts are of the same magnitude (0.5-1 arb. unit/mg). 2) The binding and elution behavior on DEAE-cellulose is similar. 3) In both cases the pH optimum (substrate 125I-BSA) is pH 7.6. 4) Both enzymes are inhibited by hemin, NEM and iodoacetate but not e.g. by leupeptin, or inhibitors of serine proteases. 5) Neither enzyme system can utilize ATP-analogs such as AMP-CPP, AMP-PCP, AMP-PNP or ATP-gamma-S. There are however also significant differences: 1) The enzyme system from cardiac muscle is fully active in the absence of ubiquitin and cannot be activated by this peptide. 2) The enzyme from cardiac muscle can degrade methylated BSA. 3) The cardiac muscle enzyme can be further purified on Sepharose 4B; the enzyme from reticulocytes is inactivated by this procedure. 4) The cardiac enzyme cannot be inactivated by ribonuclease as the reticulocyte counterpart. Although ubiquitin does not appear to play a role in the isolated ATP/Mg2-dependent proteolytic system from cardiac muscle, it is demonstrated for the first time that 125I-ubiquitin can be conjugated to a wide variety of cardiac muscle proteins in vitro in an ATP-dependent manner. Apparent molecular masses of major conjugates were: 185 kDa, 140 kDa, 85 kDa, 65 kDa, 46 kDa, 38 kDa and 36 kDa as estimated by discontinuous SDS gel electrophoresis. Addition of purified phosphorylase kinase to cardiac muscle extract changed the ubiquitination pattern by the appearance of two novel protein bands. It is concluded that the ATP/Mg2-dependent proteolytic system of cardiac muscle must be differentiated from the proteolytic system of reticulocytes mainly because of its ubiquitin-independence. Nevertheless the conjugation of 125I-ubiquitin to many muscle proteins is a strong indication for a crucial role of this interesting peptide in striated muscle.
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PMID:ATP-dependent proteolysis and the role of ubiquitin in rabbit cardiac muscle. 304 36

This study sought to determine whether the reported lead-induced inhibition of binding of the non-competitive NMDA receptor complex antagonist, MK-801, was of sufficient biological strength and relevance to produce changes in MK-801 behavioral sensitivity. Rats were chronically exposed from weaning to levels of 0, 50 or 150 ppm lead (Pb) acetate in drinking water and trained to discriminate the stimulus properties of 0.05 mg/kg MK-801 from saline at 2 months of age using a standard operant food-reinforced drug discrimination paradigm. Following acquisition of the discrimination, various doses of MK-801, of the non-competitive antagonist phencyclidine (PCP), the competitive antagonist CPP, and of NMDA, were substituted for 0.05 mg/kg MK-801 and percent MK-801 lever responding to each determined. Increasing doses of MK-801 and of PCP produced dose-related increases in MK-801 lever responding to levels exceeding 90%, whereas CPP produced levels less than 50 percent. NMDA produced primarily saline lever responding. Pb exposure was associated with MK-801 subsensitivity as indicated by downward and/or right-shifts of the MK-801 dose-effect curve, and by attenuated MK-801 lever responding following an MK-801 washout period. No Pb-related changes in sensitivity to PCP, CPP or NMDA were observed. These data provide in vivo support for the possibility that glutamatergic system changes could be involved in the behavioral toxicity produced by lead exposure.
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PMID:MK-801 subsensitivity following postweaning lead exposure. 760 48

Capsaicin in the adult animal causes antinociception due to the massive release of neurotransmitters, including substance P (SP), from primary afferent C-fibers. The results of the present study indicate that capsaicin-induced antinociception in the adult is sensitive to inhibition by dizocilpine (MK-801). The failure of a high dose (10 nmoles) of (+-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) to mimic the effect of MK-801 (1 nmole) on antinociception induced by 0.8 micrograms of capsaicin suggests that the inhibition by MK-801 is mediated by a phencyclidine (PCP) site but is not associated with NMDA activity. The inability of haloperidol (1 nmole) to affect the actions of capsaicin argues against an interaction with sigma sites. Behavioral sensitization to intrathecally administered kainic acid (KA) has been proposed to reflect similar neuronal activity to that underlying pain transmission. KA sensitization is inhibited by pretreatment with capsaicin (0.8 microgram) or SP(1-7) (10 nmoles) and the influence of MK-801, CPP and haloperidol on these inhibitory effects of capsaicin and SP(1-7) were identical to those on capsaicin-induced antinociception. These data are consistent with the hypothesis that the antinociceptive effect of capsaicin in the adult is similar to that of the N-terminus of SP, both of which involve a pathway sensitive to MK-801 but not mediated by NMDA-type activity.
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PMID:MK-801 inhibits the effects of capsaicin in the adult mouse by an action involving phencyclidine (PCP) sites not linked to NMDA activity. 769 10

The sympathetic nervous system has been shown to exert a trophic influence on vascular smooth muscle cells (VSMC). Therefore, we studied the growth-regulating effects of the sympathetic cotransmitters ATP, neuropeptide Y (NPY), and norepinephrine (NE). ATP in concentrations of 1-100 microM greatly increased the incorporation of [3H]thymidine in VSMC from rat aorta and vena cava. ATP also increased cell number and total protein content. The maximal effect on [3H]thymidine incorporation was greater than for epidermal growth factor (20 ng/ml) or insulin (1 microgram/ml) and approximately one-half that of 10% fetal calf serum. The potency series of other nucleotides and analogues of ATP was ATP > beta, gamma-methyleneATP (AMP-PCP) > ADP > adenosine > alpha, beta- methyleneATP (AMP-CPP) > 2-methylthioATP, indicating involvement of a P2 receptor, however, it does not meet proposed pharmacological criteria of either the P2x or P2y subclass. Several proposed P2 receptor antagonists were without effect. The effect of ATP could be mediated by a "nucleotide receptor," since UTP also stimulated [3H]thymidine incorporation. In our model, there was a strong correlation between the mitogenic effects of ATP, AMP-CPP, AMP-PCP, and UTP and their ability to stimulate influx of extracellular Ca2+ (Ca2+o). Moreover, the mitogenic effect of ATP was increased by high concentrations of Ca2+o. Taken together with data showing the lack of involvement of several other second-messenger systems, this indicates a critical role for Ca2+o in mediating the mitogenic effects of ATP. Amiloride, known to inhibit the action of several growth factors, also inhibited ATP-induced mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitogenic effects of ATP on vascular smooth muscle cells vs. other growth factors and sympathetic cotransmitters. 769 83

The present study was performed to assess the utility of excitatory amino acid (EAA) antagonists as analgesia agents. The antinociceptive activity of various classes of EAA antagonists was assessed in mechanical and thermal flexion reflexes tests, as well as in the formalin test. Additional testing assessed the motor dysfunction associated with antinociceptive dose levels of the agents used, by examining placing, grasping and righting reflexes, as well as occurrences of balance loss during locomotion. No antinociceptive activity was observed on any of the nociceptive measures for the non-NMDA receptor antagonists CNQX or L-AP-3. High doses of the non-competitive (PCP-site) NMDA receptor antagonist MK-801 and the allosteric-glycine receptor antagonist 7-CKA produced antinociception on both the mechanical and thermal flexion reflex measures, while a high dose of the competitive NMDA receptor antagonist CPP produced antinociception only on the thermal flexion reflex measure. Hyperalgesic effects on thermal flexion reflexes were obtained with all doses of the polyamine receptor antagonist ARCA, and with the highest dose of the allosteric-glycine receptor antagonist FICA. Formalin nociceptive behaviours were significantly reduced only by high doses of competitive (APV) and non-competitive (MK-801) NMDA receptor antagonists. The doses of EAA receptor antagonists which produced antinociceptive effects on any of the 3 nociceptive tests also produced evidence of motor dysfunction. Both competitive NMDA receptor antagonists (APV and CPP) produced disruptions of placing, grasping and righting reflexes, while 2 of the allosteric-glycine receptor antagonists (7-CKA and DCQX) significantly disrupted placing and righting reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The utility of excitatory amino acid (EAA) antagonists as analgesic agents. I. Comparison of the antinociceptive activity of various classes of EAA antagonists in mechanical, thermal and chemical nociceptive tests. 770 8


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