RESUMO
A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicinérgicos/farmacologia , Glicina/antagonistas & inibidores , Indóis/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Ácidos Carboxílicos , Córtex Cerebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Glicina/metabolismo , Glicinérgicos/síntese química , Glicinérgicos/química , Glicinérgicos/metabolismo , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , N-Metilaspartato/farmacologia , Ratos , Receptores de Glutamato/metabolismo , Relação Estrutura-Atividade , Estricnina/farmacologiaRESUMO
A novel series of 3-carbamoylethynyl-2-carboxyindoles, antagonists acting at the strychnine-insensitive glycine binding site associated with the NMDA receptor, has been synthesised. This new versatile approach involves the introduction of a 2-chloroethenyl moiety in position C-3 with subsequent derivatisation of the terminal carboxyl group, followed by an unusual elimination of HCl to afford the ethynyl functionality. This novel series of glycine antagonists was evaluated in terms of in vitro affinity at the glycine binding site and the most potent compound was tested in vivo in the NMDA-induced convulsions model in mice.