RESUMO
The anticonvulsant properties of 1,4-benzodiazepines (BDZs), pyrazoloquinolones (CGS), 2-aryl-2,5-dihydropyridazino[4, 3-b]indol-3(3H)-ones (PIs) 1 1i 1d 1f 1e 1b 1c 1h, and 1a, the latter being inactive against audiogenic seizures. Some PIs 1 and abecarnil showed anticonvulsant properties against seizures induced by PTZ with a potency lower than that observed in audiogenic seizures. The pharmacological actions of 1d, 1f, and 1i were significantly reduced by a treatment with flumazenil (8.24 micromol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of 1d, 1f, and 1i was also evaluated against seizures induced by two beta-carbolines namely methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), in DBA/2 mice: they gave better protection against seizures induced by beta-CCM than the ones by DMCM. The potency of various BDZs and PIs as inhibitors of specific [3H]flumazenil binding to neuronal membranes, was also evaluated. The radioligand binding study, carried out on stable cell lines expressing definite combinations of benzodiazepine receptor subunits, demonstrated that 1b, 1e, 1d, and 1h have preferential interaction with alpha(1), beta(3), gamma(2), receptor subtypes.
Assuntos
Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/farmacologia , Indóis/farmacologia , Cetonas/farmacologia , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Flumazenil/metabolismo , Flumazenil/farmacologia , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Atividade Motora/efeitos dos fármacos , Pirazóis/farmacologia , Convulsões/prevenção & controle , Sinaptossomos/metabolismoRESUMO
A series of 2-aryl-3-chloro-2H-pyridazino[4,3-b]indoles, 2-aryl-3-methoxy-2H-pyridazino[4,3-b]indoles, and 2-aryl-2,5-dihydroindeno[1,2-c]pyridazino-3(3H)-ones has been prepared and tested for their ability to inhibit the [3H]flunitrazepam binding to the central benzodiazepine receptor. SAR are presented and discussed in comparison with existing pharmacophore models.
Assuntos
Indóis/síntese química , Piridazinas/síntese química , Receptores de GABA-A/efeitos dos fármacos , Ligação de Hidrogênio , Indóis/química , Indóis/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Piridazinas/química , Piridazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The in vitro antibacterial and antifungal activities of a series of pyridazinoindolonic acids II against some selected representative of Gram-positive, Gram-negative bacteria and fungi have been investigated. Some interesting observations among the structural features necessary for high antibacterial activity are presented and discussed.
Assuntos
Antibacterianos/farmacologia , Indóis/farmacologia , Piridazinas/farmacologia , Antibacterianos/síntese química , Indóis/síntese química , Estrutura Molecular , Piridazinas/síntese químicaRESUMO
A large series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)ones (PIs) carrying properly selected substituents at the indole and N2-phenyl rings was prepared and tested as central benzodiazepine receptor (BZR) ligands and potential (anti)convulsant agents. Stereoelectronic requirements for high receptor affinity were detected by means of 2-D and 3-D QSAR analyses. BZR affinities and pharmacological profiles of the compounds were examined in comparison with some other pyridazinoindolones recently described by us and with pyrazoloquinoline (PQ) analogues. An anticonvulsant activity greater than PQs was generally observed for PIs. Notably, in the test of audiogenically induced seizures, one compound showed a potency comparable to that of diazepam.
Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Indóis/química , Indóis/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Receptores de GABA-A/metabolismo , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Ligação de Hidrogênio , Indóis/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Pentilenotetrazol/farmacologia , Piridazinas/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Análise de Regressão , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of amidinosulfonic acids IIIa-f, analogs of taurine and homotaurine, was synthesized by reacting 2-aminoethane or 3-aminopropane sulfonic acid with lactim ethers Ia-c and then cyclized to sultams IVa-c and Vd-f. The effects of some selected amidinosulfonic acids III on membrane ionic conductances of rat skeletal muscle are described.
Assuntos
Músculo Esquelético/efeitos dos fármacos , Taurina/análogos & derivados , Taurina/síntese química , Amidinas/síntese química , Amidinas/farmacologia , Animais , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/farmacologia , Taurina/farmacologiaRESUMO
A series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones 5 were prepared and evaluated for their ability to inhibit radioligand binding to BZR, and to prevent sound and pentylenetetrazole (PTZ) induced seizures in mice. The biological and pharmacological results are discussed in the light of some recently proposed pharmacophore models and compared through molecular orbital and molecular modeling studies to those obtained from the close pyrazoloquinoline analogs 6.