dizocilpine-maleate and remacemide

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.

Topics: 2-Amino-5-phosphonovalerate; Acetamides; Animals; Animals, Newborn; Apoptosis; Behavior, Animal; Central Nervous System; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Neurotoxicity Syndromes; Rats; Receptors, N-Methyl-D-Aspartate

The effects of chronic administration of MK-801 (NMDA-receptor antagonist) and remacemide (sodium channel blocker) on monkey learning of several brain function tasks was assessed in juveniles (nine months old). Low (LO) and high (HI) doses of both drugs were given orally each day for 18 months. There were no adverse effects of any treatment on tests of short-term memory or motivation. HI doses of both MK-801 and remacemide delayed acquisition of a visual discrimination task (the remacemide effect was much greater). HI doses of remacemide alone severely disrupted learning task acquisition and this effect lasted for several months after dosing. Thus, in monkeys, chronic blockade of NMDA receptors is relatively well tolerated, whereas blockade of sodium channels (perhaps in conjunction with NMDA receptor blockade) has long-term-perhaps permanent-consequences. To further explore the roles of NMDA receptors and sodium channels in these effects, MK-801, phenytoin (sodium channel blocker), or both were administered to rats and the acquisition of tasks similar to those used in the monkey study were assessed. Dosing began at weaning and continued for nine months. Throughout the study, HI MK-801 subjects exhibited impaired performance in all tasks. Some effects of MK-801 were blocked completely by phenytoin. In the rat, blockade of sodium channels was well tolerated but blockade of NMDA receptors had significant and long-term (permanent?) adverse consequences. These data contrast markedly with those obtained for the monkey and suggest, at least for some drug classes, that the rat might not be a good predictor of effects in primates.

Topics: Acetamides; Animals; Brain; Cognition; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Haplorhini; Humans; Learning; Neuroprotective Agents; Neuropsychological Tests; Rats; Receptors, N-Methyl-D-Aspartate; Sodium Channel Blockers

The effects of the anticonvulsant remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its metabolite AR-R12495AA [(+/-)-1-methyl-1, 2-diphenylethylamine-monohydrochloride] on primary afferent synaptic transmission were assessed in the young rat spinal cord in vitro. Stimulation of dorsal roots at A- and C-afferent intensity elicited a dorsal root-evoked ventral root potential (DR-VRP) with a slowly decaying phase. Repetitive stimuli (2 Hz) produced summation of slow potentials and a cumulative ventral root depolarization (CVRD), a form of wind-up. Remacemide and AR-R12495AA antagonized the DR-VRP slow peak t(1/2) decay and slow phase total duration at drug concentration of > or =25 microM. AR-R12495AA was approximately 2-fold more potent than remacemide. The most potent action was against the slow phase duration with IC(50) values of 157 and 60 microM for remacemide and AR-R12495AA, respectively. Both drugs at concentrations of > or =100 microM attenuated the DR-VRP fast peak amplitude (IC(50) = 253 and 142 microM, respectively). The amplitude of CVRD was reduced by remacemide and AR-R12495AA (IC(50) = 195 and 111 microM, respectively). MK-801 reduced DR-VRP fast peak amplitude (IC(50) = 58 microM), slow peak t(1/2) decay (IC(50) = 60 microM), slow phase duration (IC(50) = 50 microM), and CVRD amplitude (IC(50) = 91 microM). In behavioral studies, AR-R12495AA (i.p.) reduced the mechanical hyperalgesia and paw swelling that followed hind paw injection of carrageenan or Freund's complete adjuvant. These electrophysiological and behavioral data indicate further studies should be conducted on the efficacy of remacemide and AR-R12495AA as putative analgesics.

Topics: Acetamides; Acute Disease; Afferent Pathways; Animals; Animals, Newborn; Anticonvulsants; Chronic Disease; Dizocilpine Maleate; Electric Stimulation; Electrophysiology; Excitatory Amino Acid Antagonists; Hyperalgesia; In Vitro Techniques; Inflammation; Phenethylamines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Nerve Roots; Synaptic Transmission

The anticonvulsant and neuroprotective properties of remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide] and its active des-glycine metabolite [(+/-)-1-methyl-1,2-diphenylethylamine] may result in part from blockade of N-methyl-D-aspartate (NMDA) receptors. The blocking actions of the remacemide enantiomers and their des-glycinates were investigated in whole cell voltage-clamp recordings from cultured rat hippocampal neurons and in binding studies with [3H]dizocilpine in rat forebrain membranes. (+/-)-Remacemide caused a rapid and reversible inhibition of NMDA-evoked current; the R(+)- and S(-)-enantiomers were roughly equipotent (IC50 values at -60 mV, 67 and 75 microM, respectively). In contrast, the block by the S(+)- and R(-)-des-glycine analogs was slower, more potent and occurred in a stereoselective fashion (IC50 values, 0.7 and 4 microM). The block by S(+)-des-glycine remacemide was strongly use- and voltage-dependent, and, in addition, could be occluded by Mg++, indicating that it occurs by an open channel mechanism. In contrast, the block by R(+)-remacemide was only partially voltage-dependent, suggesting that it occurs by both channel blocking and nonchannel blocking (allosteric) mechanisms. Support for an allosteric mechanism was obtained in nonequilibrium [3H]dizocilpine binding studies where it was observed that 100 microM R(+)-remacemide slowed the dissociation of the radioligand [whereas 10 microM S(+)-des-glycine remacemide did not]. Neither R(+)-remacemide nor S(+)-des-glycine remacemide inhibited currents evoked by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate or gamma-aminobutyric acid. We conclude that des-glycine remacemide is a potent and selective channel blocking NMDA receptor antagonist, whereas remacemide is weaker and inhibits NMDA receptors by both channel blocking and nonchannel blocking actions.

Topics: Acetamides; Animals; Anticonvulsants; Binding Sites; Cells, Cultured; Dizocilpine Maleate; Hippocampus; Kinetics; Membrane Potentials; N-Methylaspartate; Neurons; Neuroprotective Agents; Phenethylamines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, GABA-B; Receptors, N-Methyl-D-Aspartate; Spermine; Tritium

The neuroprotective actions of remacemide and its anticonvulsant metabolite 1,2-diphenyl-2-propylamine monohydrochloride (desglycinylremacemide; DGR) a low-affinity NMDA receptor antagonist, were investigated using primary rat cortical neuronal cultures. Exposure of cortical cultures to NMDA (100 microM) for 15 min killed 85% of the neurons during the next 24 h. This neurotoxicity was blocked in a concentration-dependent manner by adding DGR (5-20 microM), but not its remacemide precursor (10-100 microM), to the cultures during the time of NMDA exposure. This suggests that the neuroprotective, as well as the anticonvulsant, activity of remacemide is mediated by DGR. Neuroprotective concentrations of DGR also inhibited two of the principal acute effects of NMDA. DGR (5-20 microM) prevented the loss of membrane-associated protein kinase C (PKC) activity that developed by 4 h after transient exposure to 100 microM NMDA and reduced the NMDA-triggered increases in intracellular free Ca2+ concentration ([Ca2+]i) by up to 70%. By contrast, remacemide (50 and 100 microM) did not prevent the NMDA-induced loss of PKC activity or reduce the [Ca2+]i responses. These data suggest that DGR protection against NMDA-mediated toxicity in cultured cortical neurons is associated with a reduction of NMDA-triggered [Ca2+]i surges and a prevention of the loss of membrane-associated PKC activity. In addition, the inhibition of NMDA-triggered [Ca2+]i responses by DGR was qualitatively different from the inhibition of these responses by the high-affinity NMDA-receptor antagonists MK-801 and phencyclidine. This may be a consequence of DGR's lower affinity for the NMDA receptor.

Topics: Acetamides; Animals; Calcium; Calcium Channel Blockers; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Intracellular Membranes; N-Methylaspartate; Neurons; Neuroprotective Agents; Osmolar Concentration; Phencyclidine; Protein Kinase C; Rats; Rats, Sprague-Dawley

The dizocilpine-like discriminative stimulus effects of a variety of channel blocking (uncompetitive) N-methyl-D-aspartate (NMDA) receptor antagonists were examined in rats trained to discriminate dizocilpine (0.17 mg/kg, i.p) from saline in a two-lever operant procedure. The dissociative anesthetic-type NMDA antagonists dizocilpine (ED50 0.05 mg/kg), phencyclidine (ED50 3.4 mg/kg) and ketamine (ED50 14 mg/kg) showed complete substitution without producing significant decreases in response rates, whereas dexoxadrol (ED50 4.3 mg/kg) also produced complete substitution with a concomitant decrease (35%) in response rate. Similarly, the low-affinity antagonist memantine resulted in complete substitution (ED50 9.7 mg/kg) at doses that significantly reduced (68%) the response rate. All other low-affinity antagonists resulted in either partial or no substitution for the discriminative stimulus effects of dizocilpine at doses that significantly decreased average response rates. These include (ED50 values in parentheses) remacemide (29 mg/kg), the remacemide metabolite 1,2-diphenyl-2-propylamine (ARL 12495) (14 mg/kg), phencylcyclopentylamine (25 mg/kg), dextromethorphan (46 mg/kg), (+/-)-5-aminocarbonyl-10,11-dihydro -5H-dibenzo-[a,d]cyclohepten-5,10-imine (ADCI; no substitution) and levoxadrol (no substitution). We conclude that low-affinity uncompetitive NMDA antagonists have discriminative stimulus properties distinct from dissociative anesthetic-type uncompetitive NMDA antagonists. The lowest-affinity antagonists show virtually no substitution for dizocilpine, whereas the relatively more potent low-affinity antagonists (such as memantine) exhibit greater substitution, but complete substitution is obtained only at rate-reducing doses.

Topics: Acetamides; Analysis of Variance; Anesthetics, Dissociative; Animals; Conditioning, Operant; Dextromethorphan; Dioxolanes; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Male; Memantine; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate

Quantitative receptor autoradiography was used to examine the regional binding characteristics of a diverse group of N-methyl-D-aspartate (NMDA)-receptor channel blockers that varied in potency 10(5)-fold. Full competition curves were generated in each of six brain regions for 11 different compounds. MK-801 was the most potent compound studied, with an IC50 of approximately 10 nM in the forebrain regions and 24 nM in the cerebellar granule cell layer (p < 0.05). The binding affinities of nine of the 11 compounds examined were significantly different in cerebellar granule cell layer than in forebrain regions. In addition, the apparent Hill slopes of five of the compounds were significantly different in cerebellum compared with forebrain. That the rank order of drug potencies in cerebellar diverges from that in forebrain suggests that cerebellar NMDA-receptor ion channels differ pharmacologically from those in forebrain. There was a general trend that drugs known to be well tolerated in humans (remacemide hydrochloride and its metabolites, amantadine, budipine, and memantine) had lower affinities than compounds with severe neurobehavioral or psychotomimetic effects. Moreover, all of the compounds known to be well tolerated in humans had a significantly higher affinity in the cerebellum than in forebrain regions, in contrast to MK-801, 1-[1-(2-thienyl)cyclohexyl]-piperidine hydrochloride (TCP), phencyclidine (PCP), and ketamine, which had lower affinities in cerebellum. Our results are consistent with the notion that low affinity (rapid kinetics) and, possibly, subunit specificity (as indicated by distinct regional pharmacologies) may be important determinants of the clinical tolerability of NMDA-receptor channel blockers.

Topics: Acetamides; Animals; Antiparkinson Agents; Autoradiography; Binding, Competitive; Brain; Dizocilpine Maleate; Ion Channels; Phencyclidine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Tissue Distribution

One of the primary undesired effects of anticonvulsant medication is an impairment in cognitive function, such as new learning ability. The purpose of the present study was to compare the effects of remacemide hydrochloride [(+/-)-2-amino-N-(1-methyl-1,2,-diphenylethyl)acetamide monohydrochloride] and FPL 15896AR [(+)-alpha-phenyl-2-pyridine-ethanamide] to a number of anticonvulsant agents on an operant acquisition baseline. Remacemide hydrochloride is currently in clinical trials for epilepsy and FPL 15896AR is under development. In the present procedure, fasted, experimentally naive rats were placed into operant chambers in which food pellets were initially available under a Fixed-Ratio 1 (FR1) schedule of food presentation, and as lever pressing progressed, the FR value incremented. All drugs were tested in multiples of three and ten times their respective ED50 values against maximal electroshock-induced seizure (MES) following p.o. administration. The drugs tested varied widely in their ability to disrupt acquisition of the lever-pressing task. Remacemide hydrochloride and a structurally related analog, FPL 15896AR, did not disrupt acquisition. Clonazepam, lamotrigine, MK-801, phenobarbital, felbamate, phenytoin, and carbamazepine increased the number of hours required to achieve FR3 (emit more than 100 responses) with respect to vehicle control performance. Of these, clonazepam, MK-801 and phenytoin produced robust enough disruption to result in significantly fewer reinforcers delivered over the 14-h operant session.

Topics: Acetamides; Animals; Anticonvulsants; Clonazepam; Conditioning, Operant; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Learning; Male; Phenytoin; Pyridines; Rats

1. In this study the effect of FPL 12495AA, the desglycinyl metabolite of remacemide hydrochloride and dizocilpine (MK-801), on potassium- and veratridine-stimulated release of neurotransmitter amino acids from mouse cortical slices was investigated. 2. Veratridine (20 microM) and potassium (60 mM) produced a preferential release of glutamate and aspartate. Potassium-stimulated release was calcium-dependent, while veratridine-stimulated release was only partially affected by removal of calcium from the medium. 3. FPL 12495AA significantly inhibited veratridine- and potassium-stimulated release of glutamate and aspartate. Lower concentrations of FPL 12495AA were needed to inhibit veratridine-stimulated release of glutamate (12.5 microM) than potassium-stimulated release (100 microM). 4. Dizocilpine significantly inhibited veratridine- and potassium-stimulated release of glutamate and aspartate at concentrations of 100 microM and above. 5. FPL 12495AA and dizocilpine both have an affinity for the ion channel subsite of the N-methyl-D-aspartate (NMDA) receptor. The reduction of potassium-stimulated release of glutamate and aspartate by FPL 12495AA and dizocilpine is probably due to NMDA receptor blockade. 6. FPL 12495AA inhibited veratridine-stimulated release at a concentration of 12.5 microM while dizocilpine was effective only at a concentration of 100 microM. This difference in efficacy is probably due to the higher affinity of FPL 12495AA compared to dizocilpine at the veratridine-binding site on the sodium channel.

Topics: Acetamides; Animals; Anticonvulsants; Aspartic Acid; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Phenethylamines; Potassium; Veratridine

Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N-methyl-D-aspartate receptor ion channel. In normal rats and monoamine-depleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK-801. When monoamine-depleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5-40 mg/kg, orally) caused a dose-dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100-200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa-carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa-carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa-carbidopa was substantially better than levodopa-carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N-methyl-D-aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acetamides; Analysis of Variance; Animals; Anticonvulsants; Antiparkinson Agents; Brain; Carbidopa; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Levodopa; Macaca mulatta; Male; Motor Activity; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Reserpine; Time Factors

Remacemide hydrochloride ((+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)- acetamide hydrochloride or FPL 1292AA) is a novel compound undergoing clinical trials for patients with generalized tonic/clonic and complex partial epilepsy. Remacemide exhibits efficacy against maximal electroconvulsive shock (MES) in rodents and seizures elicited by N-methyl-D,L-aspartate (NMDLA) in mice. Using rat synaptic membrane fractions, remacemide was shown to possess relatively weak noncompetitive binding to the ionic channel site of the NMDA (N-methyl-D-aspartic acid) receptor complex. With the hypothesis that activity against NMDLA-elicited seizures might be reflected by transformation to a more active metabolic species, the aim of the present study was to evaluate potential pharmacological effects of the 9 identified metabolites of remacemide which were all found in human and dog urine. Moreover, specific entities were recognized in plasma (including the rat's), as well as dog and rat cerebrospinal fluid. Five putative metabolites were also examined. A major route of metabolic transformation of remacemide in rats yields the formation of a pharmacologically active more potent desglycine derivative, namely FPL 12495 (+/-). Potency over the parent compound is revealed in the MES test in mice and rats, the NMDA-induced convulsions/mortality test in mice, and especially involving in vitro displacement of MK801 binding to the channel subsite of the NMDA receptor. The S isomer (FPL 12859) of this desglycinate is even more potent, while the R isomer is less potent than the corresponding racemate. Unlike the non-competitive NMDA antagonist, MK801, these desglycinates did not prevent kindled seizures. Three other identified metabolites show efficacy in the mouse and rat in vivo tests, namely the N-hydroxy-desglycinate (FPL 15053) and the p-hydroxy-desglycinates (FPL 14331 and FPL 14465). FPL 15053 exhibited modest activity in all tests. The only in vivo activity exhibited by the 2 p-hydroxy-desglycinates was evidenced in the MES test following i.p. and i.v. dosing. However, FPL 14331 was active in the MK801 binding assay. An oxoacetate metabolite, PFL 15455, failed to demonstrate any biological activity. Of potential metabolites tested 2 beta-hydroxy-desglycinates (FPL 14991 and FPL 14981) displayed modest activity in the MES test, however, only FPL 14981 prevented NMDLA-induced convulsions/mortality in mice and was 2-fold more active regarding MK801 binding. The hydroxy-methyl de

Topics: Acetamides; Animals; Anticonvulsants; Dizocilpine Maleate; Electroshock; Kindling, Neurologic; Male; Mice; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures