RESUMEN
Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100+ years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-free with the existing medications. In addition, the clinical use of the existing AEDs is restricted by their side-effects, including the teratogenicity associated with valproic acid that restricts its use in women of child-bearing age. Thus, there is an unmet clinical need to develop new, effective AEDs. In the present study, a novel class of carbamates incorporating phenethyl or branched aliphatic chains with 6-9 carbons in their side-chain, and 4-benzenesulfonamide-carbamate moieties were synthesized and evaluated for their anticonvulsant activity, teratogenicity and carbonic anhydrase (CA) inhibition. Three of the ten newly synthesized carbamates showed anticonvulsant activity in the maximal-electroshock (MES) and 6 Hz tests in rodents. In mice, 3-methyl-2-propylpentyl(4-sulfamoylphenyl)carbamate(1), 3-methyl-pentan-2-yl-(4-sulfamoylphenyl)carbamate (9) and 3-methylpentyl, (4-sulfamoylphenyl)carbamate (10) had ED50 values of 136, 31 and 14 mg/kg (MES) and 74, 53, and 80 mg/kg (6 Hz), respectively. Compound (10) had rat-MES-ED50 = 13 mg/kg and ED50 of 59 mg/kg at the mouse-corneal-kindling test. These potent carbamates (1,9,10) induced neural tube defects only at doses markedly exceeding their anticonvuslnat-ED50 values. None of these compounds were potent inhibitors of CA IV, but inhibited CA isoforms I, II and VII. The anticonvulsant properties of these compounds and particularly compound 10 make them potential candidates for further evaluation and development as new AEDs.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Carbamatos/uso terapéutico , Anhidrasas Carbónicas/uso terapéutico , Ácidos Carboxílicos/uso terapéutico , Convulsiones/tratamiento farmacológico , Sulfanilamidas/uso terapéutico , Animales , Anticonvulsivantes/química , Anticonvulsivantes/toxicidad , Carbamatos/química , Carbamatos/toxicidad , Anhidrasas Carbónicas/química , Anhidrasas Carbónicas/toxicidad , Ácidos Carboxílicos/química , Ácidos Carboxílicos/toxicidad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Excitación Neurológica/efectos de los fármacos , Excitación Neurológica/fisiología , Masculino , Ratones , Defectos del Tubo Neural/inducido químicamente , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Relación Estructura-Actividad , Sulfanilamida , Sulfanilamidas/química , Sulfanilamidas/toxicidad , Teratógenos/química , Teratógenos/toxicidadRESUMEN
p-Aminobenzene sulphonyl morpholine, compound 82/208, was evaluated for acute toxicity and anticonvulsant action in mice against tonic seizures induced by supramaximal electroshock and pentylene tetrazole and strychnine induced seizures and for its effect on blood pressure and respiration in cat. Diphenyl hydantoin (DPH) was used as reference standard. Compound 82/208 exhibited anticonvulsant activity against electroshock induced seizures and PTZ induced tonic seizures in mice. The compound had several distinct advantages over DPH in experimental evaluation in mice.