RESUMO
A series of thiazepines has been studied as new ligands for the benzodiazepine binding site of the GABAA receptor. Compounds with high affinity and weak selectivity regarding alpha beta3gamma2, alpha2beta3gamma2, alpha3beta3gamma2, and alpha5beta3gamma2 subtypes were found. The pharmacophore is discussed based on experimental and theoretical results. The thiazepine sulfur atom was found to be able to act as hydrogen bond acceptor.
Assuntos
GABAérgicos/síntese química , GABAérgicos/farmacologia , Piranos/química , Receptores de GABA-A/efeitos dos fármacos , Tiazepinas/química , Cromatografia Líquida de Alta Pressão , Células HEK293 , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes/química , Padrões de Referência , Espectrofotometria Ultravioleta , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of new indazol-3-ol derivatives was synthesized. Some of these compounds exhibit interesting anti-inflammatory activities in various models of inflammation. 5-Methoxy-1-[quinoline-2-yl-methoxy)-benzyl]-1H-indazol-3-ol (27) strongly inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid catalyzed by 5-lipoxygenase (IC50 = 44 nM). 27 also inhibits the contraction of sensitized guinea pig tracheal segments (IC50 = 2.9 microM). In guinea pigs treated with 27 (1 mg/kg i.p.) 2 h before antigen provocation, there was a marked inhibition (47%) of the antigen-induced airway eosinophilia. After topical application of 1 microgram/ear 27 inhibits the arachidonic acid induced mouse ear edema (41%).
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Indazóis/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Eosinofilia/tratamento farmacológico , Cobaias , Técnicas In Vitro , Indazóis/farmacologia , Camundongos , Células Tumorais CultivadasRESUMO
Starting from the corresponding acetophenone and glycine derivatives, a series of new 3-aminopyrroles was synthesized in few steps. Using this procedure with hydrazine and hydroxylamine instead of the glycinates provides access to 3-aminopyrazoles and 5-amino 1,2-oxazoles. The various derivatives were tested for anticonvulsant activity in a variety of test models. Several compounds exhibit considerable activity with a remarkable lack of neurotoxicity. 4-(4-Bromophenyl)-3-morpholinopyrrole-2-carboxylic acid methyl ester, 3, proved to be the most active compound. It was protective in the maximal electroshock seizure (MES) test in rats with an oral ED50 of 2.5 mg/kg with no neurotoxicity noted at doses up to 500 mg/kg. Compound 3 blocks sodium channels in a frequency-dependent manner. The essential structural features which could be responsible for an interaction with an active site of the voltage-dependent sodium channel are established within a suggested pharmacophore model.