RESUMO
A series of pyrrolo[3,2-c]quinoline derivatives were synthesised and evaluated as inhibitors of selected enzymes of the kynurenine pathway. 7-Chloro-3-methyl-1H-pyrrolo[3,2-c]quinoline-4-carboxylic acid (7a) was found to be a relatively potent and selective inhibitor of kynurenine-3-hydroxylase (KYN-3-OHase). A molecular modelling study showed a good superimposition of 7a with PNU-156561 and kynurenine the natural substrate of KYN-3-OHase.
Assuntos
Inibidores Enzimáticos/síntese química , Oxigenases de Função Mista/antagonistas & inibidores , Pirróis/síntese química , Quinolinas/síntese química , Animais , Inibidores Enzimáticos/farmacologia , Quinurenina 3-Mono-Oxigenase , Fígado/enzimologia , Estrutura Molecular , Pirróis/farmacologia , Quinolinas/farmacologia , RatosRESUMO
Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.
Assuntos
Alanina/síntese química , Anticonvulsivantes/síntese química , Benzilaminas/síntese química , Convulsões/prevenção & controle , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Benzilaminas/química , Benzilaminas/farmacologia , Bicuculina , Desenho de Fármacos , Eletrochoque , Indicadores e Reagentes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Picrotoxina , Equilíbrio Postural/efeitos dos fármacos , Equilíbrio Postural/fisiologia , Ratos , Ratos Endogâmicos , Convulsões/induzido quimicamente , Convulsões/etiologia , Relação Estrutura-Atividade , EstricninaRESUMO
A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.
Assuntos
Imidazóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Íleo/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Modelos Moleculares , Estrutura Molecular , Músculos/efeitos dos fármacos , Ratos , Receptores 5-HT3 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismoRESUMO
The synthesis of new 2-imidazol(in)yl-alkyl derivatives of 2,3,3a,4-tetrahydro-1H-imidazo[5,1-c][1,4]benzoxazin-1-one is reported. Some compounds of the series have shown high affinity for alpha 2 receptors, high alpha 2/alpha 1 selectivity and alpha 2 antagonism in vitro (vas deferens). Owing to their selective alpha 2-antagonism associated to a novel structure, compounds 8 and 20 have been selected for further biological investigation as potential antidepressants.
Assuntos
Antagonistas Adrenérgicos alfa/síntese química , Imidazóis/síntese química , Oxazinas/síntese química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculos/efeitos dos fármacos , Norepinefrina/farmacologia , Oxazinas/química , Oxazinas/farmacologia , Ratos , Ratos Endogâmicos , Ducto Deferente/efeitos dos fármacosRESUMO
A series of 7-oxaaporphine derivatives was prepared. The compounds were evaluated as dopaminergic agents. None of them showed either affinity for dopamine receptors or activity in vivo in the climbing behavior (mice) and turning behavior (6-hydroxydopamine-lesioned rats) tests. The lack of activity is tentatively related to the effect of the oxygen atom on the pKa of these molecules.
