Comparative anticonvulsant activity of N-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives in rodents

The anticonvulsant activity of competitive 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F)-quinoxaline (NBQX) and noncompetitive 2,3-benzodiazepines and tetrahydroisoquinolines (THIQs) AMPA/kainate receptor antagonists, was tested in different experimental seizure models and compared with diazepam, a conventional antiepileptic drug acting on GABAergic neurotransmission. In particular, the compounds were evaluated against audiogenic and maximal electroshock seizures (MES) test and pentetrazol (PTZ) seizures model, and all of them showed protective action. In addition, NBQX, 2,3-benzodiazepines and THIQs, but not diazepam, were also protective against clonic and tonic seizures and lethality induced by kainate, AMPA and ATPA, but were ineffective against NMDA-induced seizures. Only 2,3-benzodiazepines and some THIQs were able to affect 4-aminopyridine- and mercaptopropionic-acid-induced seizures. The duration of anticonvulsant action of 33 micromol/kg of some 2,3-benzodiazepines and THIQs was also investigated in DBA/2 mice, a strain genetically susceptible to audiogenic seizures, and it was observed that the derivative THIQ-10c, possessing an acetyl group at the N-2 and a chlorine atom on the C-1 phenyl ring, showed higher anticonvulsant activity and longer-lasting protective effects.     

Synthesis and anticonvulsant activity of some alkanamide derivatives

A group of N-phenylacetamide, N-phenylpropanamide and N-benzylamide derivatives bearing 5-membered heterocyclic rings such as pyrazole, 1,2,4-triazole and imidazole rings at omega position were synthesized and their anticonvulsant activity was evaluated in the maximal electroshock test. The results indicated that the 1,2,4-triazole ring leads to superior activity than the pyrazole ring and inserting a CH2 group into the anilide structure leading to N-benzyl derivatives did not change the anticonvulsant activity, but caused a noticeable decrease in duration of action. The most active compound was 2-(1H-1,2,4-triazole-1-yl)-N-(2,6-dimethylphenyl)acetamide.     

Synthesis and anticonvulsant activity of novel and potent 2,3-benzodiazepine AMPA/kainate receptor antagonists.

We have previously shown that 1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (3) possess marked anticonvulsant properties and antagonize seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) in analogy to the structurally related 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA/kainate receptor antagonist. We now report the synthesis of 3-(N-alkylcarbamoyl)-1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (4a-h) and 1-aryl-3, 5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepine-4-thiones (5a-c). The activity of all compounds, intraperitoneally (ip) injected, was evaluated against audiogenic seizures in DBA/2 mice and against seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in Swiss mice. Some of the new compounds 4 and 5 showed remarkable anticonvulsant activity, and their toxicity, as evidenced by the rotarod test, is lower than that of 1. The time course of anticonvulsant activity of derivatives 4b and 5b,c was studied and compared to that of 1 and 3b,c. Compounds 4a,b and 5a-c antagonize seizures induced by AMPA and kainate (KA) and their anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 3c, 4b, and 5c to antagonize KA-evoked currents in primary cultures of granule neurons was tested and compared with that of the parent compounds 1 and 1-(4-aminophenyl)-3, 4-dihydro-4-methyl-3-methylcarbamoyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine (2, GYKI 53655).     

Synthesis and anticonvulsant activity of some new dioxolane derivatives

In this study, ten 2-acetylnaphthalene derivatives with a dioxolane structure were synthesized and screened for their anticonvulsant activities. Dioxolane derivatives were prepared by the reaction with appropriate ethanone, glycol and p-toluensulphonic acid. The structures of the compounds were elucidated by IR, 1H-NMR and elemental analysis. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES) test and subcutaneous metrazol (ScMet.) test. The rotarod toxicity test was used for the assessment of neurological deficits. According to the activity studies compound 6 was found neurotoxic, compounds, 1, 4, 5, 7-9 were found protective against MES and 7-10 were found protective against ScMet. Compounds 2 and 3 were found inactive.     

Effects of GYKI 52466 and some 2,3-benzodiazepine derivatives on hippocampal in vitro basal neuronal excitability and 4-aminopyridine epileptic activity

In order to determine whether the anticonvulsant effect of 2, 3-benzodiazepines is also displayed in a model of in vitro epilepsy, such as the "epileptiform" hippocampal slice, we studied the effects of 2,3-benzodiazepine 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxe-5H 2,3-benzodiazepine hydrochloride (GYKI 52466) and some new 2,3-benzodiazepine derivatives on CA1 basal neuronal excitability and on CA1 epileptiform burst activity produced by 4-aminopyridine in rat hippocampal slices. The results showed that GYKI 52466 affected basal neuronal excitability as evidenced by its influence on the magnitude of the CA1 orthodromic-evoked field potentials. 2,3-Benzodiazepines showed their antiepileptic effect also in an in vitro model of experimental epilepsy. The effects of the new 2,3-benzodiazepine derivatives suggest that the methylenedioxidation in positions 7 and 8 of the 2,3-benzodiazepine ring is the main structural modification for the antiepileptic effect of 2,3-benzodiazepines to take place.     

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.     

Molecular requirement for anticonvulsant activity in a series of thiazolo-1,4-benzodiazepine derivatives and comparison with classical benzodiazepines

• 1.1. The behavioural and anticonvulsant effects of several thiazolo[3,2-d][1,4]benzodiazepines (TBZ) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures.
• 2.2. Anticonvulsant effects on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) were evaluated in DBA/2 mice placed singly under a perspex dome.
• 3.3. Hypothermic activity was observed after the highest doses of the benzodiazepines studied.
• 4.4. In addition, some TBZ were examined for anticonvulsant properties with respect to clonus induced by pentylenetetrazol.
• 5.5. Our study demonstrated that some thiazolobenzodiazepine derivatives were more potent than clobazam, desmethylclobazam and chlordiazepoxide, and less potent than diazepam, desmethyldiazepam and alprazolam.
• 6.6. In the series of tricyclic benzodiazepines, thiazole nucleus fusion to the “d” edge of the 7-membered ring results in an effective increase of the energy barrier for the heptatomic system reversal, and is probably responsible for, jointly with the lack of C=N double bonds, lower activity with respect to the 1,4-benzodiazepine precursors.
• 7.7. The potency of various thiazolobenzodiazepine derivatives as inhibitors of specific [³H]flunitrazepam binding to membranes from cerebellum or hippocampus was evaluated.
• 8.8. All tested compounds produced concentration-dependent inhibition of [³H]flunitrazepam binding.
• 9.9. The pharmacological activity of TBZ2, the most active compound of this series, was significantly reduced by treatment with flumazenil (2.5 mg/kg i.p.), suggesting clear involvement of a benzodiazepine mechanism in the anticonvulsant activity of these compounds.

     

Synthesis and anticonvulsant activity of some new series of pyrrole derivatives

A new series of compounds 3a–f were synthesized from condensation method. Newly synthesized compounds were established by IR, ¹H NMR, ¹³C NMR, mass spectral and elemental analysis. Synthesized compounds 3a–f were screened for anticonvulsant activity. The compound 2,2′-({3-methyl-5-[2-phenylethenyl]-1H-pyrrole-2,4-diyl}dicarbonyl)dihydrazinecarbothioamide 3a showed significant activity compared with other compounds 3b–f against pentamethylene tetrazole-induced seizures.     

Synthesis and anticonvulsant activity of some new hexahydropyrimidine-2,4-dione derivatives

In this study, twelve new hexahydropyrimidine-2,4-dione derivatives were synthesized and screened for their anticonvulsant activities. All the compounds (7a-1) which have 6-arylhexahydropyrimidine-2,4-dione and N,N-disubstituted dithiocarbamate structures were prepared by the reaction with appropriate 3-(2-chloroethyl)-6-arylhexahydropyrimidine-2,4diones and the corresponding N,N-disubstituted dithiocarbamate potassium salts. The structure of the synthesized compounds was confirmed by UV, IR, 1H-NMR and elemental analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous pentetrazol (metrazol, scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 6-(4-chlorophenyl)hexahydropyrimidine-2,4-dione derivatives (7e-h) were found to be highly protective against MES and scMet. Neurotoxicity was not observed in any of the tested compounds.     

The synthesis and anticonvulsant activity of some omega-phthalimido-N-phenylacetamide and propionamide derivatives

In this study, by combining anilide and N', N'-phthaloylglycinamide pharmacophores which are known to produce potent anticonvulsant compounds, sixteen omega-phthalimido-N-phenylacetamide and propionamide derivatives bearing substituents at positions 2 or 2, 6 on N-phenyl ring have been 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 at 100 mg/kg dose level in mice. The preliminary screening results indicated that omega-phthalimido-N-phenylacetamide and propionamide nuclei have pronounced anticonvulsant activity against maximal electroshock seizure.     

Synthesis and anticonvulsant activity of some 2/3-benzoylaminopropionanilide derivatives

In this study, the synthesis and anticonvulsant properties of sixteen 2/3-benzoylaminopropionanilide derivatives were described. Molecular design of the compounds has been based on the modification of lacosamide which is a functionalized amino acid with a novel anticonvulsant activity. The structural confirmation of the title compounds was achieved by spectral and analytical data. The anticonvulsant activity profile of synthesized compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) seizure tests, whereas their neurotoxicity was examined using rotarod test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. The majority of the compounds were effective in the MES or scMet screening tests. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. Most active compounds in the series were 3, 12 and 13, which bearing 2-methyl, 2-ethyl and 2-isopropyl substituent on the N-phenyl ring, respectively.     

1,5-benzodiazepine derivatives with expected psychotropic activity

By sulfuration of 4-methyl-1H-tetrahydro-1,5-benzodiazepinone-2 (1) its 2-thione 2 was synthesized. From this compound 2-hydrazone 3 and s-triazole derivatives 4 and 5 were obtained. Screening revealed that only compound 2 showed strong inhibitory activity in the spontaneous motility test, weak synergism with hexobarbital, weak antinflammatory activity in the carrageenin test and strong analgesic activity in the hot plate test.     

The effect of substitution on anticonvulsant activity of some 5,5-diphenylhydantoin derivatives

Some 5,5-diarylhydantoins and their 3-amino derivatives were synthesized as phenytoin analogs with enhanced rotational restriction of the benzene moieties. In preliminary pharmacological tests, the compounds symmetrically substituted in the benzene rings proved practically inactive as anticonvulsants. High and prolonged activity was observed with 3-amino-5,5-diphenylhydantoin.     

Synthesis and anticonvulsant activity of some N-(benzoyl)glycinanilide derivatives

Glycine is a major inhibitory neurotransmitter and recent studies have shown that certain lipophilic glycine derivatives demonstrate anticonvulsant activity in animal epilepsy models. On the other hand, anilide is another fruitful structure for designing potential anticonvulsant agents. Ameltolide, ralitoline and some phthalimide derivatives are the examples of anilide analogs with potent anticonvulsant activity. In this study, two key structural pharmacophores were combined and a series of N-benzoylglycinanilide derivatives were designed. Their anticonvulsant activities evaluated against maximal electroshock (MES) and subcutaneous metrazole seizure tests, whereas their neurotoxicity was examined by rotarod test. The preliminary screening results indicated that majority of the compounds were effective in the MES test. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. The most active compound in the series is N-(2-((4-methoxyphenyl)amino)-2-oxoethyl)benzamide (compound 8) which bearing 4-methoxy substituent on the N-phenyl ring.     

Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives

New cyclofunctionalized 2,3-benzodiazepines characterized by a triazolone or triazindione ring fused on the "c" edge of the heptatomic nucleus have been prepared. These compounds were evaluated as potential anticonvulsant agents, and some of them proved to be more potent noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) receptor antagonists. In particular, 8,9-dimethoxy-6-(4-bromophenyl)-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-one (5b) was almost 10-fold more active than GYKI-52466 and 3.5-fold more active than Talampanel. Furthermore, 5b potently reduced AMPA-evoked currents in electrophysiological experiments.     

Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives

The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n). The bioevaluation demonstrated that most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED(50) value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 4h displayed broad-spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system.     

Synthesis and anticonvulsant activity of some benzopyranone imino derivatives of GABA and related compounds

The synthesis of some 5-hydroxy-4-imino-2,3-dihydrobenzopyran derivatives of GABA and alkylamines is described. The products were tested for their GABA-receptor binding and anticonvulsant activity in mice. Some compounds showed anticonvulsant activity. No binding to GABA receptors was observed.     

Synthesis and anticonvulsant activity of imidooxy derivatives

Previous results of anticonvulsant activity in several imidooxy carboxylates related to (aminooxy)acetic acid in young chicks, prompted an in-depth reinvestigation of these analogues in mice. A series of 22 succinimidooxy, phthalimidooxy, and naphthalimidooxy carboxylates were synthesized and evaluated for anticonvulsant activity by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS). Methyl (succinimidooxy)acetate (2d), ethyl (succinimidooxy)acetate (2e), methyl (phthalimidooxy)acetate (3d), ethyl (phthalimidooxy)acetate (3e), and ethyl 2-(phthalimidooxy)propionate (3g), which were initially found to be active as anticonvulsants in young chicks were uniformly inactive in the Phase I seizure tests involving maximal electroshock (MES), pentylenetetrazol (scMet), or neurologic toxicity toxicity (Tox). Several newer analogues, ethyl (succinimidooxy)formate (2c) and methyl 3-(phthalimidooxy)-2-methylacrylate (4h) were found to be active in the scMet (3a) or both (4h) evaluations. Most interesting was the anticonvulsant results of N-(benzyloxy)-2-azaspiro[4,4] nonane-1,3-dione (5b), which displayed anti-MES activity and a protective index (TD50/ED50) of greater than 4.5.