RESUMO
The synthesis of unsymmetrical naphth[2,3-d]imidazolium and bridged naphth[2,3-d]imidazolium derivatives and their substance P (SP) antagonist activity are described. All compounds were evaluated for their ability to displace SP from neurokinin-1 (NK-1) receptor sites using standard receptor binding methodology (rat forebrain membrane). 1,3-Diethyl-2-[3-(1,3-dihydro-1,3,3-timethyl-2H-indol-2-ylidene) -1-propenyl]-1H-naphth[2,3-d]imidazolium chloride (7a), a representative compound in this series, was further evaluated for SP antagonist activity in a guinea pig ileum contractility assay. In vivo SP antagonist activity of 7a was demonstrated using SP-induced salivation and paw edema models performed in rats.
Assuntos
Imidazóis/síntese química , Indóis/síntese química , Substância P/antagonistas & inibidores , Animais , Ligação Competitiva , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Cobaias , Íleo/fisiologia , Imidazóis/metabolismo , Imidazóis/farmacologia , Indóis/metabolismo , Indóis/farmacologia , Masculino , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores da Neurocinina-2 , Receptores de Neurotransmissores/metabolismo , Salivação/efeitos dos fármacos , Relação Estrutura-Atividade , Substância P/metabolismoRESUMO
To examine the role of each component in the heterocycle-phenyl-imidazole inotropic pharmacophore, several imidazolone derivatives, an arylimidazole, a substituted 3,4-dihydro-4-oxopyrimidine, and a quinolin-2(1H)-one derivative were prepared as structural fragments or representatives from this relationship. Tests for cardiac inotropic activity in ferret papillary muscle strips (FPM) and for inhibition of crude cAMP phosphodiesterase obtained from canine cardiac tissue suggest that, while all three components contribute significantly toward potent activity (active at less than 1 microM concentrations in FPM), any combination of two components, in approximately a preferred geometry, represents the minimal requirements for weak activity (active at less than 25 microM concentrations). No single component appears to be requisite in an absolute sense.
Assuntos
Benzoatos/farmacologia , Imidazóis/farmacologia , Contração Miocárdica/efeitos dos fármacos , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Benzoatos/síntese química , Cardiotônicos/síntese química , Cardiotônicos/farmacologia , Cães , Furões , Imidazóis/síntese química , Estrutura Molecular , Miocárdio/enzimologia , Estimulação Química , Relação Estrutura-AtividadeRESUMO
Several heterosteroids containing a dihydroethisterone skeleton were prepared and shown to displace substance P in a receptor binding assay. Further biochemical (kinetic and Scatchard analyses) and pharmacological evaluation (substance P-induced plasma extravasation and salivation in the rat) of a representative example in this series (5a) established that these compounds are competitive antagonists at the substance P receptor.