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)

Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typically small molecules that consist of a 4-benzyl- or a 4-phenylpiperidine with an omega-phenylalkyl substituent on the heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a 4-hydroxy substituent on the omega-phenyl group. In this study, the position of this 4-hydroxy substituent was transferred from the omega-phenyl group to the benzyl or phenyl group located on the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes show that high-potency antagonists at the NR1A/2B subtype are obtained employing N-(omega-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4-hydroxybenzyl)piperidine, and (+/-)-3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC(50) = 0.022 microM), 33 (IC(50) = 0.059 microM), and 40 (IC(50) = 0.017 microM), respectively. These high-potency antagonists are >1000 times more potent at the NR1A/2B subtype than at either the NR1A/2A or NR1A/2C subtypes. The binding affinities of 21 at alpha(1)-adrenergic receptors ([(3)H]prazosin, IC(50) = 0.54 microM) and dopamine D2 receptors ([(3)H]raclopride, IC(50) = 1.2 microM) are reduced by incorporating a hydroxy group onto the 4-position of the piperidine ring and the beta-carbon of the N-alkyl spacer to give (+/-)-27: IC(50) NR1A/2B, 0.026; alpha(1), 14; D2, 105 microM. The high-potency phenolic antagonist 21 and its low-potency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal electroshock-induced seizure (MES) study (ED(50) (iv) = 0.23 and 0.56 mg/kg, respectively). These data indicate that such compounds penetrate the blood-brain barrier but their MES activity may not be related to NMDA receptor antagonism.
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PMID:Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4-hydroxybenzyl)piperidines, and (+/-)-3-(4-hydroxyphenyl)pyrrolidines: selective antagonists at the 1A/2B NMDA receptor subtype. 1071 62

A series of N-aryl and N-aminoaryl 3-phenyl pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and pentetrazol seizure threshold (sc Met) tests. Structures of the novel compounds were confirmed by elemental and spectral analyses.
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PMID:Synthesis and anticonvulsant properties of new 1-phenyl and 1-phenylamino-3-phenylpyrrolidine-2,5-dione derivatives. 1223 Feb 48

A series of N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-arylpyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc.MET) tests. The most potent in the series were N-[[4-(3-chlorophenyl)-piperazin-1-yl]-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione (ED50=14.18 mg/kg) and N-[[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl]-3-(3-bromophenyl)-pyrrolidine-2,5-dione (ED50=33.64 mg/kg). Structures of the novel compounds were confirmed by elemental and spectral analyses.
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PMID:Synthesis and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-aryl pyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione. 1463 Feb 32

Based on the phenomenon of the abnormally increased transport of brain excitatory amino acids induced by the increased release of dopamine (DA) in the brain, the effects of intraperitoneal L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a non-selective excitatory amino acid transporter (EAAT) inhibitor, and (+/-)-threo-3-methylglutamic acid (MG), a specific EAAT2 inhibitor, were examined against methamphetamine (MA) and cocaine (COC) toxicity in mice. The MA (5 mg/kg)-increased activity counts, which included counts of both ambulatory and stereotyped behaviors, were attenuated by 10 and 20 mg/kg of PDC, but the COC (40 mg/kg)-increased activity counts were attenuated only by 20 mg/kg PDC. PDC (20 mg/kg) significantly attenuated both the mortality rate and the seizure score in acute MA (18 mg/kg) toxicity, but attenuated only the seizure score in acute COC (75 mg/kg) toxicity. PDC and MG (repeated doses of 5 and 10 mg/kg) attenuated the mortality rate (significant attenuation in the PDC group) and seizure score against repeated MA (12 mg/kg) toxicity, but had no effect on repeated COC (60 mg/kg) toxicity. Furthermore, MA (5 mg/kg) and COC (40 mg/kg) induced stressor-like and anxiogenic effects, the former of which were attenuated by PDC only (10 and 20 mg/kg in the MA group and 20 mg/kg in the COC group), and the latter of which were attenuated by both PDC and MG (for both drugs, 10 and 20 mg/kg in the MA group and 20 mg/kg in the COC group). Therefore, it was concluded that not only EAAT2 but also the other EAATs contributed to the occurrence of the MA-induced effects and part of the COC-induced effects, and that a non-selective EAAT inhibitor notably blocked the behavioral effects accompanying the MA-induced over-release of DA.
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PMID:Brain excitatory amino acid transporters (EAATs) and treatment of methamphetamine toxicity. 1475 Mar 60

The effect of pyrrolidine dithiocarbamate (PDTC) on kainate (KA)-induced neurotoxicity was examined in Sprague-Dawley rats. At 10 mg/kg, i.p., KA produced seizures accompanied by neuronal loss in the hippocampus and increased levels of malondialdehyde (MDA) and protein carbonyl. Pretreatment with PDTC (100 or 200 mg/kg, p.o., every 12 h x 5) blocked KA-induced neurotoxicities (seizures, increases in MDA and protein carbonyl and neuronal losses) in a dose-dependent manner. These effects were counteracted by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (25 or 50 micro g/kg, i.p.), but not by the A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1 mg/kg, i.p.) or the A(2B) receptor antagonist alloxazine (1.5 or 3.0 mg/kg, i.p.). Our results suggest that the anticonvulsant and neuroprotective effects of PDTC are mediated, at least in part, via adenosine A(1) receptor stimulation.
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PMID:Protection against kainate neurotoxicity by pyrrolidine dithiocarbamate. 1519 5

Two series of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methylpiperazin-1-yl)-propyl]-3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione derivatives were synthesized and tested for anticonvulsant activity in the maximum electroshock (MES) seizure and pentetrazole (sc PTZ) seizure threshold tests. Compounds with an aromatic ring at position-3 of pyrrolidine-2,5-dione exhibited anticonvulsant activity in the MES test. For that series of compounds, ED50 values were determined. The most potent in the series were derivatives and with a chlorine atom at position-3 or 4 of the aromatic ring. Those compounds exhibited strong anticonvulsant activity, and their ED50 values ranged from 29 to 48 mg/kg. Introduction of the spirocycloalkyl ring into the position-3 of pyrrolidine-2,5-dione made those compounds inactive.
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PMID:Anticonvulsant properties of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methyl-piperazin-1-yl)propyl] derivatives of 3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione. 1588 15

The extracellular concentration of glutamate is highly regulated by transporter proteins, due to its neurotoxic properties. Dysfunction or reverse activation of these transporters is related to the extracellular accumulation of excitatory amino acids and neuronal damage associated with ischemia and hypoglycemia. We have investigated by microdialysis the effects of the substrate and the non-substrate inhibitors of glutamate transporters, l-trans-2,4-pyrrolidine dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA), respectively, on the extracellular levels of amino acids in the rat hippocampus in vivo. In addition, we have studied the effect of both inhibitors on neuronal damage after direct administration into the hippocampus and striatum. Electroencephalographic activity was recorded after the intrahippocampal infusion of DL-TBOA or PDC. Microdialysis administration of 500 microM DL-TBOA into the hippocampus increased 3.4- and nine-fold the extracellular levels of aspartate and glutamate, respectively. Upon stereotaxic administration it induced neuronal damage dose-dependently in CA1 and dentate gyrus, and convulsive behavior. Electroencephalographic recording showed the appearance of limbic seizures in the hippocampus after DL-TBOA infusion. In the striatum it also induced dose-dependent neuronal damage. These effects were prevented by the i.p. administration of the glutamate receptor antagonists (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-iminemaleate and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline. In contrast to dl-TBOA, PDC (500 microM) induced a more discrete elevation of excitatory amino acids levels (2.6- and three-fold in aspartate and glutamate, respectively), no neuronal damage or behavioral changes, and no alterations in electroencephalographic activity. The differential results obtained with DL-TBOA and PDC might be attributed to their distinct effects on the extracellular concentration of amino acids. Results are relevant to the understanding of the role of glutamate transporters in amino acid removal or release and the induction of excitotoxic cell death.
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PMID:Differential effects of the substrate inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC) and the non-substrate inhibitor DL-threo-beta-benzyloxyaspartate (DL-TBOA) of glutamate transporters on neuronal damage and extracellular amino acid levels in rat brain in vivo. 1589 Apr 55

The synthesis, physicochemical and pharmacological properties of new N-phenylamino derivatives of 2-azaspiro[4.4]nonane-1,3-dione (8-10), 2-azaspiro[4.5]decane-1,3-dione (11-18) and 3-cyclohexyl-pyrrolidine-2,5-dione (19, 20) derivatives were described. The anticonvulsant properties of those compounds were examined by a maximal electroshock (MES) and a pentylenetetrazole (scPTZ) tests, and their neurotoxicity was determined using a rota-rod test. The most active was N-[(2,4-dichlorophenyl)-amino]-2-azaspiro[4.4]nonane-1,3-dione (9), which exhibited anti-seizure properties in the MES model at a dose of 100mg/kg in mice and at a dose of 30mg/kg in rats. To explain the possible mechanism of action, for chosen active derivatives N-[(2,4-dichlorophenyl)-amino]-2-azaspiro[4.4]nonane-1,3-dione (9), N-[(4-bromophenyl)-amino]-2-azaspiro[4.4]nonane-1,3-dione (10), N-[(2,4-dichlorophenyl)-amino]-2-azaspiro[4.5]decane-1,3-dione (12) and N-[(4-bromophenyl)-amino]-2-azaspiro[4.5]decane-1,3-dione (13) their influence on GABA(A) receptors were tested in vitro. Moreover, for all compounds obtained the lipophilic properties were determined by use of RP-HPLC method.
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PMID:Synthesis, physicochemical and anticonvulsant properties of new N-phenylamino derivatives of 2-azaspiro[4.4]nonane- and [4.5]decane-1,3-diones: part V. 1747 69

To continue our systematic SAR studies a series of N-phenylamino derivatives of 2-azaspiro[4.4]nonane-, 2-azaspiro[4.5]decane-, 6-methyl-2-azaspiro[4.5]decane-1,3-dione and 3-cyclohexylpyrrolidine-2,5-dione were synthesized and tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and subcutaneous metrazole seizure threshold (sc. Met) tests. Among those molecules the most potent were N-(4-methylphenyl)-amino-2-azaspiro[4.4]nonane-1,3-dione [V], N-(2-trifluoromethylphenyl)-amino-2-azaspiro[4.4]nonane-1,3-dione [VI], N-(3-methylphenyl)-amino-2-azaspiro[4.5]decane-1,3-dione [VIII] and N-(4-methylphenyl)-amino-6-methyl-2-azaspiro[4.5]decane-1,3-dione [XIV], which inhibited the seizures mainly in the sc. Met test. The obtained results revealed that anticonvulsant activity depended on the presence and the position of the methyl or trifluoromethyl groups at the aryl moiety, as well as the size and the manner of attachment of the cycloalkyl system at the position-3 of the pyrrolidine-2,5-dione ring.
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PMID:Synthesis and anticonvulsant properties of new N-phenylamino derivatives of 2-azaspiro[4.4]nonane, 2-azaspiro[4.5]decane-1,3-dione and 3-cyclohexylpyrrolidine-2,5-dione. Part IV. 1751 72

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. In combination with conventional antiepileptic drugs, levetiracetam, 5mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of some antiepileptic drugs studied against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by levetiracetam was greater, approximately twice, for carbamazepine, diazepam, felbamate, topiramate, gabapentin, and valproate, less for lamotrigine, phenobarbital and phenytoin. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with levetiracetam was more favourable than the combination with saline with the exception of lamotrigine, phenytoin and phenobarbital. Since levetiracetam did not significantly influence the total and free plasma and the brain levels of antiepileptics studied. In addition, levetiracetam did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, levetiracetam showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably carbamazepine, diazepam, felbamate, gabapentin, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.
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PMID:Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice. 1755 69


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