RESUMO
This report continues the in-depth evaluation of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate , 1 (ADD 196022), and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 2, two potent anticonvulsant enaminones. These compounds were evaluated employing the amygdala kindling model. Neither 1 nor 2 was active against amygdala kindled seizures, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported. Additional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg. Several active analogs have been prepared with the view to minimizing toxicity. In a special ip rat screen developed by the Antiepileptic Drug Development (ADD) Program, these newer analogs were evaluated for protection against maximal electroshock seizures (MES) at 10 mg/kg and neurotoxicity at 100 mg/kg. From this screen, several compounds were shown to be safer alternatives, the most notable was methyl 4-[(p-bromophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 13. Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a protective index (TD50/ED50) of > 67. By variation in the ring size, additional aromatic substitutions and the synthesis of acyclic analogs, these newer compounds provide a more definitive insight into the structure-activity correlation. CLOGP evaluation and molecular modeling studies are also provided to further elaborate the molecular characteristics of potential anticonvulsant enaminones.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Benzilaminas/síntese química , Ácidos Cicloexanocarboxílicos/síntese química , Cicloexilaminas , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Benzilaminas/química , Benzilaminas/farmacologia , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacologia , Excitação Neurológica/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeAssuntos
Anemia Falciforme/epidemiologia , Hipertensão/epidemiologia , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Estados UnidosRESUMO
As the availability and quality of our national data-gathering systems have increasingly been taken for granted, concern and protection for these resources have been relaxed. This has resulted in the loss of a focus for statistical policy and coordination, a diminution in the size of samples taken, a retrogression in the amount of data collected, and the neglect of social and economic research. It is the responsibility of government, labor, business, and users of data to demand a national statistical coordination that maintains quality, integrity, and independence.