RESUMO
Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Iminas/síntese química , Fármacos Neuroprotetores/síntese química , Riluzol/análogos & derivados , Riluzol/síntese química , Sulfóxidos/síntese química , Tiazóis/síntese química , Animais , Benzotiazóis , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico , Hipóxia/mortalidade , Iminas/química , Iminas/farmacologia , Injeções Intraventriculares , Masculino , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Riluzol/química , Riluzol/farmacologia , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Relação Estrutura-Atividade , Sulfóxidos/química , Sulfóxidos/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A series of 4-amino-6-chloro-2-piperazinopyrimidines were synthesized and evaluated for their ability to interact with alpha 1- and alpha 2-adrenoceptors in vitro in binding assays using [3H]WB-4101, [3H]clonidine, and [3H]idazoxan as radioligands. Some compounds were also tested as inhibitors of [3H]spiroperidol binding. Several members of this series showed high and selective affinity for alpha 2-adrenoceptors. The nature of the 4-amino substituent seems to be the most critical factor in determining the potency at these receptors.
Assuntos
Piperazinas/metabolismo , Pirimidinas/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Animais , Ligação Competitiva , Córtex Cerebral/metabolismo , Clonidina/metabolismo , Corpo Estriado/metabolismo , Dioxanos/metabolismo , Idazoxano , Ratos , Espiperona/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 30 6-chloro-2,4-diaminopyrimidines was synthesized and tested in vitro as inhibitors of [3H]spiroperidol binding. The affinity for the dopamine receptor was shown to be related to the 6-chloro-4-(N-methyl-piperazine)pyrimidine structure bearing a NH2 or NHR1 group as a substituent in position 2, provided that R1 was not an alpha branched alkyl group. The nature of the substituent in position 5 is also of importance for the affinity; 2-(benzylamino)-6-chloro-4-(N-methylpiperazino)-5-(methylthio)pyrimidine (22) is the most active member of the series. Molecular structures of three compounds were analyzed by X-ray diffraction and PCILO computation.
Assuntos
Butirofenonas/metabolismo , Pirimidinas/síntese química , Espiperona/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Fenômenos Químicos , Química , Clozapina/farmacologia , Corpo Estriado/metabolismo , Cristalografia , Haloperidol/metabolismo , Técnicas In Vitro , Conformação Molecular , Piperazinas/síntese química , Piperazinas/farmacologia , Pirimidinas/farmacologia , Ratos , Receptores Dopaminérgicos/efeitos dos fármacos , Difração de Raios XRESUMO
A series of 3-(4-piperidinylalkyl)indoles was synthesized and tested as uptake inhibitors of biogenic amines. Some of these compounds are potent and very selective in blocking the 5-hydroxytryptamine (5-HT) uptake, as evidenced by biochemical data and behavioral tests. A discussion on structure-activity relationships is given. The most interesting member of the series, indalpine, 3-[2-(4-piperidinyl)ethyl]indole (1), was selected for clinical studies.