cgp-37849 and selfotel

Effect of the new competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 137424-81-8, CGP 40116) was examined in a mongolian gerbil model of global cerebral ischemia. Effect of CGP 40116 was compared to that of another competitive NMDA antagonist, (+/-)-cis-4-phosphonomethyl-piperadine-2-carboxylic acid (CAS 110347-85-8, CGS 19755) under the same conditions. Drugs were administered intraperitoneally 30 min before bilateral carotid artery occlusion. At 4 days after the ischemia, locomotor activity was significantly higher in ischemic control mongolian gerbils in comparison with sham-operated mongolian gerbils. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the doses of 10 and 30 mg/kg significantly suppressed the increase of the motility. Seven days after ischemia, ischemic control group was still hyperactive compared to sham-operated group. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the dose of 30 mg/kg significantly reversed it. The number of survived neurons of ischemic control group was significantly less than that of sham-operated group at 7 days after ischemia. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the dose of 30 mg/kg significantly increased the number of survived neurons. It is concluded that CGP 40116 is more potent for amelioration of global cerebral ischemic damage than CGS 19755.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cell Survival; Excitatory Amino Acid Antagonists; Gerbillinae; Ischemic Attack, Transient; Male; Motor Activity; Neurons; Neuroprotective Agents; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate

The effect of the new competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 137424-81-8, CGP 40116) was examined in a cat model of focal cerebral ischemia. Effect of CGP 40116 was compared to that of another competitive NMDA antagonist, (+/-)-cis-4-phosphonomethyl-piperadine-2-carboxylic acid (CAS 110347-85-8, CGS 19755) under the same conditions. Drugs were administered intravenously 30 min before left middle cerebral artery (MCA) occlusion. After MCA occlusion for 8 h, infarction spreaded widely among caudate nucleus prepyriform cortex, amygdala and temporal lobe cortex in the ischemic hemisphere. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the dose of 30 mg/kg significantly decreased the infarcted area. CGP 40116 was effective in the frontal and central brain, although CGS 19755 showed neuroprotective effect in almost all sites. Thus, the compounds are potent neuroprotectants in focal ischemia.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain; Brain Ischemia; Cats; Cerebral Infarction; Excitatory Amino Acid Antagonists; Image Processing, Computer-Assisted; Male; Neuroprotective Agents; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate

Focal cerebral ischemia was induced in rats by permanent occlusion of the left middle cerebral artery (MCA). The cerebroprotective properties of the competitive NMDA antagonist CGP 40116 were evaluated in that model and compared to the neuroprotective effects of MK 801, D-CPPene and CGS 19755 under the same experimental conditions. Infarct volume was assessed using in vivo magnetic resonance imaging. The rank order of potency for the NMDA antagonists tested was MK 801 > CGP 40116 approximately D-CPPene > CGS 19755. CGP 40116 dose-dependently reduced the volume of cortical infarction, with an ED50 of 11 mg/kg i.v., and its cerebroprotective efficacy was comparable to that of MK 801. Neuroprotection by CGP 40116 was still apparent when treatment was started 30 minutes after MCA occlusion. It is concluded that CGP 40116 is an effective cerebroprotectant with potential clinical utility for amelioration of focal cerebral ischemic damage.

Topics: 2-Amino-5-phosphonovalerate; Animals; Blood Pressure; Brain Ischemia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Pipecolic Acids; Piperazines; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate

Injection of the N-methyl-D-aspartate receptor agonist, quinolinic acid, into the rat striatum in vivo results in the degeneration of cholinergic and GABAergic neurons, as determined seven days later using the marker enzymes, choline acetyltransferase and glutamate decarboxylase, respectively. Such damage was dose-dependently prevented by CGP 37849 or MK-801 (competitive and uncompetitive N-methyl-D-aspartate receptor antagonists, respectively) administered systemically or intrastriatally at the same time as quinolinic acid. The neuroprotective activity of CGP 37849 was associated with the D-enantiomer, CGP 40116 (ED50 7.5 mg/kg i.p.), which was approximately 1.5-fold and 3.5-fold more potent than the related compounds, D-CPPene and CGS 19755, respectively. CGP 37849 was a weaker neuroprotectant than MK-801 (ED50 0.8 mg/kg i.p) when administered systemically, but was dramatically more potent following coinjection with quinolinic acid (ED50's 0.2 and 117 nmol, respectively). When injected intrastriatally 0.5-2 h post-quinolinic acid, CGP 37849 was protective over the entire period studied, whereas MK-801 was less effective at all post-quinolinic acid injection times. The finding that CGP 37849 is neuroprotective when administered intrastriatally 1-2 h post-quinolinic acid supports the hypothesis that a period exists following excitotoxic insult in which neurons are not committed to die, and can be rescued by blockade of ongoing N-methyl-D-aspartate receptor activation. Competition studies indicated that, when coinjected with 100-400 nmol quinolinic acid into the striatum, CGP 37849 exhibited kinetics predicted of a competitive N-methyl-D-aspartate receptor antagonist (declining neuroprotective potency with increasing doses of agonist), whereas MK-801 displayed a complex picture, with weak protective activity at low doses of quinolinic acid. Following systemic administration, neither antagonist was markedly affected by the dose of excitotoxin. When given i.p. at up to 6 h post-quinolinic acid, CGP 37849 and MK-801 showed essentially identical profiles of post-insult protection; degeneration of cholinergic neurons was reduced significantly throughout the entire post-insult period, whereas GABAergic neurons were protected only when drugs were administered 2 h or earlier post-quinolinic acid. The data indicate that competitive and uncompetitive N-methyl-D-aspartate receptor antagonists are effective neuroprotectants in vivo, and that parameters such as drug li

Topics: 2-Amino-5-phosphonovalerate; Acetylcholine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Binding, Competitive; Biomarkers; Cell Death; Choline O-Acetyltransferase; Corpus Striatum; Dizocilpine Maleate; Drug Administration Schedule; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Injections; Injections, Intraperitoneal; Kainic Acid; Male; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Neurotoxins; Pipecolic Acids; Piperazines; Quinolinic Acid; Rats; Receptors, N-Methyl-D-Aspartate

The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849 (100 mg kg-1 i.p.) caused vacuolation in cortical pyramidal neurons in the posterior cingulate cortex four hours after dosing and this dose of CGP 37849 caused a pattern of limbic glucose metabolism activation similar to that seen after dizocilpine. CPP was without effect at 100 mg/kg i.p. probably due to poor brain penetration. The data indicates that the functional consequences (structural and metabolic) of NMDA receptor blockade with NMDA antagonists acting competitively at the glutamate recognition site and uncompetitively in the receptor ion channel are ultimately the same. Comparisons of the potential therapeutic window for CGS 19755 and CGP 37849 with dizocilpine (neuroprotection versus vacuolation) suggests that the window for the competitive antagonists is greater. This indicates that the potential therapeutic window for the different classes of NMDA antagonists may vary with the site in the receptor complex at which they interact.

Topics: 2-Amino-5-phosphonovalerate; Animals; Binding, Competitive; Brain; Cerebral Cortex; Glucose; Male; Neurons; Pipecolic Acids; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The behavioral effects of the competitive N-methyl-D-aspartate (NMDA) antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 17742) were compared with those of its parent compound, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 12626), and other reference agents in a variety of operant-based tasks in rodents. In mice trained to lever press under a fixed-ratio (FR) 20 reinforcement schedule, NPC 17742 was 6.2 times more potent than NPC 12626 and equipotent with the competitive NMDA antagonist [E]-2-amino-4-methyl-5-phosphono-3-penteneoic acid (CGP 37849) in reducing rates of responding. NPC 17742 was also 3.5 and 4.5 times more potent than [+-]cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755) and [+-] 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), respectively, and half as potent as 3SR, 4aRS, 6SR, 8aRS-6-(phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylate (LY 274614) in this paradigm. In rats trained to discriminate 4.0 mg/kg NPC 17742 from saline, NPC 17742 was 5.7 times more potent than NPC 12626 in substituting for NPC 17742. CGS 19755 also substituted for NPC 17742, but a maximum of only 50% NPC 17742 lever responding was observed after LY 274614 administration. In rats trained to lever press in a modified Geller-Seifter procedure, NPC 17742 and NPC 12626, like the benzodiazepine chlordiazepoxide, increased rates of punished responding. Neither tolerance nor sensitization to the anti-punishment effects were observed upon administration of NPC 17742 for 5 consecutive days. The results are consistent with NPC 17742 being a potent, systemically active compound whose behavioral effects are mediated through interaction with the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Behavior, Animal; Binding, Competitive; Dose-Response Relationship, Drug; Isoquinolines; Male; Mice; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The effect of different glutamate-receptor antagonists on the induction of cortical spreading depression of Leao and of cortical anoxic membrane depolarization were investigated in the anaesthetized rat. Spreading depression (SD), elicited by mechanical stimulation of the cortical surface, was inhibited by the non-competitive N-methyl-D-aspartate (NMDA)-receptor blocker, (+-)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imi ne maleate (dizocilpine or MK-801), (0.30 mumol kg-1 (0.10 mg kg-1)), and the competitive NMDA-receptor antagonists; cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755), (3.36 mumol kg-1 (0.75 mg kg-1)), D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), (1.20 mumol kg-1 (0.25 mg kg-1)) and its carboxylester CGP 43487, (6.30 mumol kg-1 (1.50 mg kg-1)). The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepripriate (AMPA)-receptor blocker, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), administered as an intravenous dose of 29.76 and 89.29 mumol kg-1 (10 & 30 mg kg-1), which is sufficient to block seizures and protect against ischaemic brain damage, did not inhibit spreading depression. None of the drugs utilized inhibited the anoxic membrane depolarization. The data demonstrate that NMDA-receptor activation is essential for the initiation and propagation of spreading depression, while activation of AMPA-receptors is not obligatory. The observed initiation and propagation of SD, during AMPA-receptor blockade, suggest that activation of voltage-operated ion channels may contribute to release the magnesium block of the NMDA-receptor operated channel and to the initiation of SD.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain; Cell Membrane Permeability; Cortical Spreading Depression; Dizocilpine Maleate; Electrophysiology; Excitatory Amino Acid Antagonists; Ion Channels; Male; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate