Synthesis and structure-activity studies of alkyl-substituted gamma-butyrolactones and gamma-thiobutyrolactones: ligands for the picrotoxin receptor.

A series of gamma-butyrolactones and gamma-thiobutyrolactones possessing a variety of alkyl groups and alkyl-substitution patterns was prepared and evaluated for anticonvulsant and convulsant activity. Behavioral studies performed on these compounds suggest that maximal anticonvulsant activity (against maximal electroshock and pentylenetetrazol) results when three or four carbon atoms are present at the alpha-position. For convulsant potency, a similar dependence on the size of the alkyl chain at the beta-position was observed. Additional gamma-dimethyl groups were found to increase the convulsant potency of a beta-substituted compound and to cause an alpha-substituted anticonvulsant to become a convulsant. In general, sulfur for oxygen heteroatom substitution in the alpha-substituted lactones resulted in improved anticonvulsant potency and spectrum of activity. Binding of these compounds to the picrotoxin site of the GABA receptor complex was demonstrated with a [35S]-tert-butylbicyclophosphorothionate radioligand binding assay. Measurements of brain concentrations for selected compounds supports a hypothesis that correlates binding to the picrotoxin site with the pharmacological effects of these compounds.     

Synthesis and anticonvulsant activity of 2-benzylglutarimides

A series of 2-benzylglutarimides (4) and their N-methyl analogues (5) were prepared according to the Topliss scheme for the selection of benzyl substituents to maximize anticonvulsant activity. A total of 22 such compounds were subjected to initial (phase I) screening in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazol (scMet) and in the rotorod assay for neurotoxicity. From this series of test compounds, 10 were advanced to quantitative (phase II) testing. Of these, 2-(4-chlorobenzyl)glutarimide (4b) emerged as the most promising anticonvulsant drug candidate by demonstrating both good anti-scMet and anti-MES activity combined with low neurotoxicity after intraperitoneal administration in mice. In drug differentiation tests, 4b was also effective in nontoxic doses against seizures induced by bicuculline, picrotoxin, and strychnine. When compared with the clinically useful drugs phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide, 4b exhibited an overall pharmacological profile most closely resembling that of valproate.     

Evaluation of anticonvulsant and analgesic effects of benzyl- and benzhydryl ureides

The anticonvulsant effects of benzyl- and benzhydryl ureides in mice models of seizures (maximal electroshock seizure test, pentylenetetrazol test, picrotoxin-induced seizure test) and the influence on spontaneous locomotor activity has been assessed. Furthermore, the analgesic effect of ureide derivatives was studied in the hot-plate test in mice. Selected compounds were investigated for their in vitro interaction with adenosine receptors as well as the benzodiazepine binding site of GABA(A) receptors. This study demonstrated the strong anticonvulsant activity of several ureides in electrically or chemically induced seizure models, and structure-activity relationships were discussed. 1-Benzyl-3-butyrylurea (9) was found to be equipotent to ethosuximide in the pentylenetetrazol test with regard to the number of attacks as well as the time of the onset of seizures. The ureide 9 also revealed the highest protective activity against seizures in the other models, maximal electroshock seizure and picrotoxin test. Moreover, 1-benzyl-3-butyrylurea was not neurotoxic at doses up to 200 mg/kg. Benzylureides 8-10 showed affinity to the adenosine A1 receptors at low micromolar concentrations. However, the apparent anticonvulsant activity in different seizure models does not appear to result from direct activation of adenosine A1 receptors or GABA(A) receptors, respectively. In the hot-plate test, the majority of investigated compounds exhibited analgesic activity. Again, compound 9 was superior to the other substances investigated, suggesting a potential therapeutic value of that ureide derivative.     

N-phenyl-N'-pyridinylureas as anticonvulsant agents

A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol. The overall pharmacological profile suggests that 37 would be of therapeutic use in the treatment of generalized tonic-clonic and partial seizures. Compound 37 was selected for Phase 1 clinical trials.     

Synthesis and anticonvulsant evaluation of some new 2-benzylsuccinimides.

A series of 2-benzylsuccinimides (4a-f) were prepared for evaluation as potential anticonvulsants. Primary (Phase I) screening of these compounds indicated that succinimides 4d and 4e, containing lipophilic (+ pi), electron-withdrawing (+ sigma) phenyl substituents, were the most effective in controlling seizures induced by maximal electroshock (MES) and subcutaneous pentylenetetrazol (scMet). Compounds 4a, 4c, and 4d showed activity against scMet-induced seizures equal to that of their 2-phenylsuccinimide analogues and were somewhat more effective in the MES test. In quantitative (Phase II) testing, when administered ip in mice, 4d and 4e both demonstrated anticonvulsant potency superior to that of the prototype drug (ethosuximide) by the MES and scMet assays. However, they also exhibited greater neurotoxicity than ethosuximide in the rotorod test.     

2′,4′-二氯苯基哒嗪衍生物的抗小鼠癫痫作用

本文对2′,4′-二氯苯基哒嗪衍生物对几种实验性癫痫模型的对抗作用进行了研究,其中化合物Ⅰ和Ⅱ对最大电休克发作实验(MEST),戊四唑(Met)印防己毒素发作和荷包牡丹碱发作等四种实验性癫痫模型均有很强的对抗作用,强于苯妥英钠,苯巴比妥和卡马西平,但也显示中枢抑制作用,预防指数不高,化合物Ⅲ和Ⅳ对这四种动物惊厥模型亦有较强的对抗作用,均大大强于丙戊酸钠和乙琥胺,其中化合物Ⅲ的中枢神经系统毒性较低,抗MEST的预防指数高达23.4.     

Interaction of felbamate and diazepam against maximal electroshock seizures and chemoconvulsants in mice.

The anticonvulsant effects of felbamate alone or in combination with diazepam were investigated against maximal electroshock-, pentylenetetrazol-, isoniazid- and bicuculline-induced seizures in mice. A single subprotective dose of felbamate, a dose which offers no protection to animals when combined with diazepam, enhanced the protective effects of diazepam against seizures induced by electroshock, pentylenetetrazol and isoniazid, as measured by significant reduction of ED50 values. However, felbamate failed to significantly affect the protective action of diazepam against bicuculline. Felbamate does not interact directly with the GABA-benzodiazepine-ionophore complex. Thus the enhancement of anticonvulsant activity of diazepam by felbamate against maximal electroshock and pentylenetetrazol may involve an indirect effect at benzodiazepine receptors. The anticonvulsant action of felbamate against isoniazid does not seem to involve benzodiazepine receptors and may be due to reversing the inhibitory effect of isoniazid on glutamate decarboxylase (GAD) activity. The interaction between felbamate and diazepam may also involve other mechanisms.     

Sex differences in sensitivity to pentylenetetrazol but not in GABAA receptor binding.

Female rats have a higher threshold than males for seizures induced by the convulsant pentylenetetrazol, a GABAA receptor-chloride channel complex blocker. No sex difference was observed for the anticonvulsant activities of ethanol or diazepam to protect against pentylenetetrazol seizures. Ovariectomy reduces the pentylenetetrazol seizure threshold of females to that of males. In contrast, females have a lower threshold than males to electroshock seizures. Pentylenetetrazol receptors were compared in males and females and gonadectomized animals by binding of several radioligands to the GABAA receptor complex. No differences were found for these four groups of animals in the binding of [3H]flunitrazepam to the benzodiazepine sites and [35S]t-butyl bicyclophosphorothionate ([35S]TBPS) to the chloride channel/convulsant sites in membrane homogenates, nor for allosteric modulation of binding by GABA, the steroid anesthetic alphaxalone, or the benzodiazepine Ro 5-4864. In tissue section autoradiography, no difference was observed for these same assays nor for the binding of [3H]muscimol in the presence and absence of alphaxalone in several major regions. We conclude that circulating female sex hormones, possibly neurosteroid metabolites of progesterone, known to interact directly with the GABAA receptor complex, are involved in the sex differences in pentylenetetrazol seizure susceptibility.     

Anticonvulsant activity of delta9-tetrahydrocannabinol compared with three other drugs.

Delta9-tetrahydrocannabinol (THC) was compared with diphenylhydantoin (DPH), phenobarbital (PB) and chlordiazepoxide (CDP) using several standard laboratory procedures to determine anticonvulsant activity in mice, i.e., the maximal electroshock test (MES), and seizures induced by pentylenetetrazol, strychnine and nicotine. In the MES test, THC was the least potent and DPH the most potent blocker of hind limb tonic extensor convulsions whereas THC was the most potent and DPH the least potent in increasing the latency to this response and in preventing mortality. Seizures and mortality induced by pentylenetetrazol or by strychnine were enhanced by THC and DPH and were blocked by PB and CDP. In the test with nicotine, none of the four anticonvulsant agents prevented seizures; DPH was the only one which failed to increase latency; THC and DPH were less potent than PB and CDP in preventing mortality. THC most closely resembled DPH in the tests with chemical convulsant agents, but a sedative action of THC, resembling that of PB and CDP, was indicated by low ED5 0 for increased latency and for prevention of mortality in the MES test.     

Anticonvulsant action of 1,3-dimethyl-5-aminoadamantane

Summary The anticonvulsant actions of memantine (1,3-dimethyl-5-aminoadamantane) have been evaluated in mice (seizures induced by maximal electroshock, pentylenetetrazol, bicuculline, picrotoxin, 3-mercaptopropionic acid and N-methyl-d,l-aspartic acid) and in photosensitive baboons, Papio Papio (clonic responses to intermittent photic stimulation). Memantine, 5–20 mg/kg, raised the threshold for electroconvulsions and protected mice against the tonic hind limb extension in pentylenetetrazol-, bicuculline-, picrotoxin-and 3-mercaptopropionic acid-induced seizures, but was ineffective against the clonic phase of chemically-induced seizures. In the baboons, no protection against photomyoclonic responses was observed within 5 h after the intravenous administration of memantine, 1–9 mg/kg. Amantadine, 100 mg/kg, reduced the protective effect of memantine against electroconvulsions. Apomorphine, haloperidol, pimozide, spiroperidol and bicuculline did not modify the anticonvulsant activity of memantine in electroconvulsions. These studies demonstrate an anticonvulsant action of memantine in rodents and suggest that dopaminergic mechanisms do not contribute to its mechanism of action.     

Evaluation of Antiseizure Activity of Essential Oil from Roots of Angelica archangelica Linn. in Mice

In the present study, the effect of essential oil of the root of Angelica archangelica Linn. was evaluated against electrically and chemically induced seizures. The seizures were induced in mice by maximal electroshock and pentylenetetrazol. The effect of essential oil of the root of Angelica archangelica on seizures was compared with standard anticonvulsant agents, phenytoin and diazepam. The essential oil of the root of Angelica archangelica suppressed duration of tonic convulsions and showed recovery in maximal electroshock induced seizures while it delayed time of onset of clonic convulsions and showed mortality protection in pentylenetetrazol induced seizures. The essential oil of the root of Angelica archangelica also produced motor impairment at the antiseizure doses. The study indicated that the essential oil exhibited antiseizure effect. The antiseizure effect may be attributed to the presence of terpenes in the essential oil.     

Synthesis and anticonvulsant activity of some N-phenyl-2-phtalimidoethanesulfonamide derivatives

In this study, inspired by the structures of the taltrimide, 2-phthalimidoethanesulphonamide, and the anilide pharmacophore known to be synthetically produced anticonvulsant compounds, fifteen N-phenyl-2-phtalimidoethanesulfonamide derivatives bearing substituents with diverse electronic and hydrophobic features on N-phenyl ring were synthesized. The structural confirmation of the title compounds was achieved by interpretation of spectral and analytical data. The anticonvulsant activity of the title compounds was determined against maximal electroshock seizure in mice at a dose level of 100 mg/kg. The preliminary screening results indicated that the exchange of the N-isopropyl moiety for an N-phenyl ring in the taltrimide molecule abolished the anticonvulsant activity. However, introducing certain substituents, such as nitro, methyl, and chloro, into the N-phenyl ring lead to more active compounds in comparison to the unsubstituted derivatives.     

A new homologous series of anticonvulsants: phenyl alcohol amides. Synthesis and pharmacological evaluation

The anticonvulsant activity of a homologous series of phenyl alcohol amides is described. (+-)-2-Hydroxy-2-phenylbutyramide (1), (+-)-3-hydroxy-3-phenylpentanamide (2) and (+-)-4-hydroxy-4-phenylhexanamide (3) were prepared and tested for their anticonvulsant profile and neurotoxicity. 1, 2 and 3 exhibited a broad profile of anticonvulsant activity and a similar significant activity in the seizures provoked by maximal electroshock, pentetrazol, 4-aminopyridine, bicuculline and thiosemicarbazide, but in the strychnine and picrotoxin tests, the protection was variable. The rotarod ataxia test was used to evaluate their neurotoxicity. In this test 2 possesses the lowest neurotoxicity.     

Studies on the involvement of dopamine D-1 and D-2 receptors in the anticonvulsant effect of dopamine agonists in various rodent models of epilepsy

Dopamine agonists with different selectivity for dopamine D-1 and D-2 receptors in the brain were tested for their effects: on thresholds for maximal electroshock seizures in mice and rats and for pentylenetetrazol-induced clonic seizures in mice; on seizures induced by air blast stimulation in gerbils, and on seizures induced by amygdala-kindling in rats. The mixed D-1/D-2 agonist apomorphine exerted anticonvulsant effects in all models except kindling. In gerbils and mice, the anticonvulsant action of apomorphine could be antagonized by the D-2 selective dopamine antagonist sulpiride. When injected alone, sulpiride exerted no significant effect on seizure activity. The preferential D-2 receptor agonists lisuride and (+)-PHNO [+)-4-propyl-9-hydroxynaphthoxazine) differed in their profile of action. Both compounds displayed anticonvulsant efficacy in gerbils, while only lisuride proved capable of reducing kindled seizure severity. (+)-PHNO increased the threshold for electroconvulsions in mice while lisuride was ineffective in this respect or even decreased the threshold. The reverse was obtained in regard to electroshock seizures in rats. The threshold for seizures induced by pentylenetetrazol in mice was increased significantly by lisuride but not by (+)-PHNO. The selective dopamine D-1 receptor agonist SKF 38393-A exerted no anticonvulsant effect in any seizure test except a moderate increase of the electroconvulsive threshold in mice. In contrast, the dopamine precursor L-DOPA (injected after pretreatment with carbidopa) proved capable of reducing seizure activity in all models. In mice, the increase in the threshold for maximal electroshock seizures induced by L-DOPA was significantly reduced by sulpiride, which also attenuated the anticonvulsant effect of L-DOPA in gerbils. Collectively, the data indicate that dopamine D-2 receptors mediate the anticonvulsant effect of dopamine agonist and, at least in part, of L-DOPA whereas D-1 receptors seem not to be involved.     

Influence of some convulsant agents on the protective activity of a novel antiepileptic drug, felbamate, against maximal electroshock in mice

The aim of this study was to evaluate effects of strychnine, as well as bicuculline and picrotoxin on the anticonvulsant action of felbamate against maximal electroshock (MES)-induced seizures in mice. Strychnine (up to 0.5 mg/kg), bicuculline (up to 2 mg/kg) and picrotoxin (3 mg/kg) did not affect the seizure threshold. However, strychnine (0.25-0.5 mg/kg) and picrotoxin (3 mg/kg) impaired the protective activity of felbamate against MES. It may be concluded that GABAergic inhibition and strychnine-insensitive glycine receptor-mediated events may contribute to the anticonvulsant activity of felbamate.     

Comparison of the Effects of Propofol and Thiopental on the Pattern of Maximal Electroshock Seizures in the Rat

The anticonvulsant effects of propofol and thiopental (thiopentone) were determined by measuring the durations of the various phases of maximal electroshock seizures in the rat. Five min. after intraperitoneal administration of subanaesthetic (6.25, 12.5 and 25 mg/kg) and 50 mg/kg doses of propofol, the 2 highest doses abolished both tonic hindlimb extensor phases (full and partial extension) in all rats and decreased the duration of the total tonic phases of the seizure. Although the lowest dose produced no effect, the 12.5 mg/kg dose decreased the duration of both the full and partial tonic extensor phases and increased the duration of tonic flexion, showing that even this low dose had anticonvulsant activity. Subanesthetic doses of thiopental (5, 10 and 20 mg/kg) produced similar changes in the maximal electroshock seizures except that even the lowest dose also significantly decreased the duration of total extension and total tonus. Postseizure depression was prolonged only by the highest dose of propofol. Thus, even low doses of either propofol or thiopental, that produced only minimal behavioural effects, had marked anticonvulsant effects against electrically induced convulsions in the rat. No evidence of enhanced convulsant maximal electroshock seizures patterns was observed at any dose.     

Search for potential anticonvulsant drugs: part I. Synthesis of 2-phenyl-3-benzimidazolyl/-alkyl (alkyl-aryl)--quinazolin (3H) -4-one

By the condensation of 2-phenyl-3-carboxy alkyl/aryl-quinazolin (3H)-4-one and substituted (unsubstituted o-phenylenediamine, fifteen new 2-phenyl-3-benzimidazolyl(-alkyl/alkyl-aryl) -quinazolin (3H)-4-ones were prepared. All the fifteen compounds were tested for anticonvulsant activity in mice against pentylenetetrazol. A good protection was obtained by most of the compounds.     

Synthesis and anticonvulsant activities of 4-N-substituted arylsemicarbazones

A series of 4-N-substituted arylsemicarbazones with increased lipophilicity were synthesized and evaluated for anticonvulsant activity. The compounds provided significant protection against maximal electroshock induced seizures (MES) and seizures indicated by sc pentetrazole administration (sc PTZ) at 300 mg/kg after 0.5 h. The compounds 8 and 4 were active in MES and sc PTZ indicated seizure. The study has shown that introduction of alkyl (ethyl) at the terminal amino group and alkoxy (methoxy) moiety at the distal aryl ring led to increased activity and decreased toxicity.     

Spiro[4.5] and spiro[4.6] carboxylic acids: cyclic analogues of valproic acid. Synthesis and anticonvulsant evaluation

Spiro[4.5]decane-2-carboxylic acid (12a), spiro[4.5]decane-2,2-dicarboxylic acid (11a), spiro[4.6]undecane-2-carboxylic acid (12b), spiro[4.6]undecane- 2,2-dicarboxylic acid (11b), and spiro[4.6]undecane-2-acetic acid (13) were synthesized by an improved method and evaluated for anticonvulsant activity. These analogues were synthesized to evaluate the role of the carboxylic acid group as an essential substituent in valproic acid (di-n-propylacetic acid, 1). Carbocyclic spiranes are known to resist metabolic alteration so that any activity elicited by these compounds would be due to the carboxylic acid function and not to any metabolic change. Spiro[4.6]undecane-2-carboxylic acid (12b) was the most active analogue tested and the pentylenetetrazol and picrotoxin evaluations of 12b compared favorably to 1. However, 12b failed to provide adequate protection against maximal electroshock seizures, bicuculline, or strychnine in mice. Possible reasons for these results are discussed.     

NMDA antagonist properties of gamma-L-glutamyl-L-aspartate demonstrated on chemically induced seizures in mice

In order to determine the gamma-L-glutamyl-L-aspartate (gamma-LGLA) site of action in excitatory amino acids (EAA) systems, we studied the gamma-LGLA anticonvulsant activity against seizures induced in mice by pentylenetetrazol, picrotoxin and EAA agonists. The mice were protected against seizures induced by pentylenetetrazol (80 mg/kg s.c.) and picrotoxin (2.75 mg/kg s.c.) after intraperitoneal administration of gamma-LGLA with two significant peak effects around the doses of 0.25 and 200 mumol/kg as revealed by the dose-response curves obtained in both experiments. Use of an intracerebroventricular co-injection procedure showed that gamma-LGLA dose dependently suppressed the seizures induced by NMDA (1 nmol/mouse) with a maximal effect at 80 nmol/mouse but, at the same dose, it only slightly suppressed seizures induced by kainate (0.3 and 0.8 nmol/mouse) or by quisqualate (18.5 nmol/mouse). The anticonvulsant activity of gamma-LGLA on these chemically induced seizures is consistent with an antagonistic action of gamma-LGLA on NMDA receptor subtypes.