Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 derivative of remacemide (FPL 13592) and its desglycinate (FPL 15112) prevented MES-induced convulsions only after i.v. administration; only the desglycine derivative displaced MK801 binding.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide. 138 19

The anticonvulsant activity of ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED50 values generally within the range of 5.0-30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50-100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.
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PMID:ucb L059, a novel anti-convulsant drug: pharmacological profile in animals. 145 32

The properties of [3H]clonazepam, [3H]diazepam and [3H]zolpidem (N,N,6[trimethyl-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-3-acetamide hemitratrate) binding to synaptic membranes of cerebellum, cortex, olfactory bulb, striatum and spinal cord of rat were compared to the binding properties of [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. In the cerebellar, cortical and olfactory bulb membranes, the density of high-affinity binding sites of all these tritiated benzodiazepine (BZ) ligands is almost identical. In contrast, in the striatum, the density of [3H]clonazepam and [3H]zolpidem binding sites is approximately 60 and 30%, respectively, of the density of [3H]diazepam, [3H]flunitrazepam or [3H]flumazenil sites. In spinal cord membranes, the number of high-affinity binding sites of [3H]clonazepam and [3H]zolpidem is less than 20% of the number of binding sites for [3H]diazepam, [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. Moreover, the displacement of [3H]flunitrazepam from spinal cord membranes by clonazepam and zolpidem was characterized by high IC50 values and Hill slopes significantly less than 1. Because [3H]BZ ligand binding in the spinal cord is enhanced by gamma-aminobutyric acid (GABA), these data suggest that different regions of the rat central nervous system may contain different GABA-BZ receptor subtypes. The different pharmacological properties of clonazepam, diazepam and zolpidem (i.e., regarding their ability to enhance bicuculline seizure threshold, to decrease locomotor activity, to induce ataxia or to elicit anticonflict action) further support the concept that in the rat central nervous system preferential occupancy of heterogeneous GABAA receptors by these drugs can be related to their effects on behavior.
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PMID:gamma-Aminobutyric acidA receptor heterogeneity in rat central nervous system: studies with clonazepam and other benzodiazepine ligands. 184 29

Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).
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PMID:Preparation and anticonvulsant activity of a series of functionalized alpha-heteroatom-substituted amino acids. 187 41

(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanone (1) was found to have an antipsychotic-like profile in behavioral tests predictive of antipsychotic efficacy but, unlike available antipsychotic agents, did not bind in vitro to dopamine receptors. Upon further evaluation, 1 was found to cause clonic seizures in aged rodents. An examination of related structures revealed that 5-(substituted aminoacetamide) analogues of 1 shared this novel pharmacology and did not cause seizures. The synthesis and pharmacological evaluation of this series of compounds are described. Two compounds, 2-(diethylamino)acetamide (25) and 2-[[3-(2-methyl-1-piperidinyl)propyl]-amino]acetamide (38), were selected for examination in secondary tests. Like known antipsychotics both compounds reduced spontaneous locomotion in mice at doses that did not cause ataxia and inhibited conditioned avoidance selectively in both rats and monkeys. Unlike known antipsychotics neither 25 nor 38 elicited dystonic movements in haloperidol-sensitized cebus monkeys, a primate model of antipsychotic-induced extrapyramidal side effects. Biochemical studies indicated that these compounds act via a nondopaminergic mechanism. Neither 25 nor 38 bound to dopamine receptors in vitro or caused changes in striatal dopamine metabolism in vivo. In addition, they did not raise serum prolactin levels as do known antipsychotics. Although adverse animal toxicological findings have precluded clinical evaluation of these agents, the present results indicate that it is possible to identify at the preclinical level nondopaminergic compounds with antipsychotic-like properties.
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PMID:(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-fluorophenyl)methanones . A series of novel potential antipsychotic agents. 287 84

Involvement of the kappa opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.c.v. administration of the kappa agonists U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), U69,593 (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl)benzeneacetamide) or PD117,302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]thiophene-4-acetamide), 50 and 150 micrograms/5 microliter each, dose-dependently decreased the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mg/kg s.c.) also attenuated the seizure activity in this model. The specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 micrograms/5 microliters i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opioids acting through kappa receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific mu opioid receptor agonist D-Ala2-N-methyl-Phe4-Gly5-ol-enkephalin (DAMGO, 0.7 microgram/5 microliters i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.
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PMID:Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats. 777 81

2-Amino-N-(1,2-diphenylethyl)-acetamide-hydrochloride (FPL 13950) was profiled preclinically in rodents for efficacy against convulsions, as well as for acute safety/behavioral observations. FPL 13950 exhibited good oral efficacy and duration of action with respect to prevention of seizures elicited by maximal electroshock-shock in both rats and mice. Tolerance to protection against maximal electroshock and hexobarbital-induced sleep-time was not evident after subchronic drug administration. FPL 13950 also prevented convulsions/mortality in mice after i.v. dosing with N-methyl-D, L-aspartate, however, it was ineffective against other types of chemically induced convulsions, as well as bicorneal kindling. High oral doses produced neural impairment in both mice and rats and hyperactivity in rats. Sequential administration of yet higher doses elicited tonic/clonic convulsions culminating in death. During i.v. infusion of metrazol in mice, high i.p. doses of FPL 13950 shortened the latency to first twitch and clonus. No increase in the startle response or phencyclidine-like behavior was evident after oral dosing in rats.
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PMID:Anticonvulsant efficacy/safety properties of 2-amino-N-(1,2-diphenylethyl)acetamide hydrochloride. 779 Oct 72

The general pharmacological properties of a novel cognition-enhancing agent, nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM-9384, CAS 77191-36-7) were investigated, and the following results were obtained. 1. Central nervous system: Nefiracetam showed depressant activities (such as ataxia) on general behavior (mice), and inhibited spontaneous locomotor activity, rota-rod and traction performances (mice) and polysynaptic potential of the spinal reflex (rats), and potentiated pentobarbital anesthesia (mice). The drug inhibited electroshock-induced seizure at relatively low doses, but did not affect chemoshock-induced seizure (mice). Nefiracetam failed to show analgesic activity in the tail pinch test, but inhibited the acetic acid-induced writhing syndrome (mice). An inhibitory pattern in the electroencephalogram was observed (cats). Nefiracetam had little or no effect on body temperature (rats). 2. Respiratory and cardiovascular systems: Nefiracetam induced transient decreases in blood pressure, left ventricular pressure and LV dp/dt max at higher doses (dogs). 3. Autonomic nervous system: Nefiracetam had no influence on pupil size (rabbits). The drug induced no significant effect on the pressor response to norepinephrine or depressor response to acetylcholine, but inhibited the contractile response of the nictitating membrane to preganglionic cervical sympathetic nerve stimulation at the highest dose (dogs). 4. Gastrointestinal system: Nefiracetam inhibited gastrointestinal propulsion (mice), gastric emptying rate and gastric secretion (rats) at higher doses. Nefiracetam produced no apparent damage in the gastric mucosa, and had no effect on bile secretion (rats). 5. Isolated smooth muscle: Nefiracetam had no effect on the resting tonus of isolated ileum, whereas it inhibited the contractile response to acetylcholine, histamine, serotonin, nicotine and BaCl2 at higher concentrations (guinea pigs). Nefiracetam had no effect on the resting tonus or the serotonin-induced contraction of stomach fundus (rats). The drug had no effect on the resting tonus or the norepinephrine-induced contraction of vas deferens, but tended to inhibit the contraction induced by nerve stimulation (guinea pigs). Nefiracetam had little or no effect on the resting tonus or oxytocin-induced contraction of virgin uterus, or on spontaneous contraction of pregnant uterus (rats). Nefiracetam did not affect the resting tonus of trachea, whereas it inhibited isoproterenol-induced relaxation at the highest concentration (guinea pigs). Nefiracetam had no chronotropic effect in isolated atria, but showed a slight negative inotropic effect at the highest concentration (guinea pigs). 6. Miscellaneous: Nefiracetam slightly decreased urinary volume, whereas it did not affect urinary electrolyte excretion (rats).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:General pharmacological profile of the new cognition-enhancing agent nefiracetam. 801 90

Methodology used for the comparative chemical analyses of two illicit cocaine seizures, and its application in a successful criminal prosecution, is described. A description of events leading to the arrest of the defendant and an overview of the jury trial are provided. Illicit cocaine, found in the defendant's suitcase and wallet, was subjected to chemical derivatization and three distinct gas chromatographic methods for the detection and relative quantitation of cocaine manufacturing impurities/by-products. The cocaine impurities included cis- and trans-cinnamoylcocaine, the isomeric truxillines and the hydroxycocaines. Among the cocaine manufacturing byproducts detected were benzoylecgonine, ecgonine methyl ester, ecgonine, N-benzoylnorecgonine methyl ester and N-norcocaine. Chemical derivatization of the cocaine samples was accomplished using heptafluorobutyric anhydride and N,O-bis(trimethylsilyl)acetamide. The derivatized impurities/by-products were subjected to capillary gas chromatographic analysis using both flame ionization and electron-capture detectors. The comparative chemical analyses provided a positive correlation between the suitcase and wallet cocaine samples.
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PMID:The anatomy of a cocaine comparison case: a prosecutorial and chemistry perspective. 826 76

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.
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PMID:Effects of anticonvulsants in a novel operant learning paradigm in rats: comparison of remacemide hydrochloride and FPL 15896AR to other anticonvulsant agents. 853 72


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