RESUMO
A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.
Assuntos
Benzimidazóis/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Fármacos Neuroprotetores/síntese química , Propionatos/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Arteriopatias Oclusivas/complicações , Benzimidazóis/química , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Ligação Competitiva , Encéfalo/metabolismo , Encéfalo/patologia , Doenças das Artérias Carótidas/complicações , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , Modelos Moleculares , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Organofosfonatos , Propionatos/química , Propionatos/metabolismo , Propionatos/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/metabolismo , EstereoisomerismoRESUMO
Rational drug design utilizing a receptor homology model of the human muscarinic M1 receptor led to the discovery of the highly potent (Ki = 2 nM), efficacious, and in vivo functionally-selective M1 agonist, WAY-132983.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Agonistas Muscarínicos/química , Agonistas Muscarínicos/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Receptores Muscarínicos/metabolismo , Administração Oral , Animais , Células CHO/metabolismo , Carbacol/química , Carbacol/metabolismo , Carbacol/farmacologia , Córtex Cerebral/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Simulação por Computador , Cricetinae , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Macaca mulatta , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Moleculares , Fosfatidilinositóis/metabolismo , Conformação Proteica , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor Muscarínico M1 , Receptores Muscarínicos/química , Salivação/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologiaRESUMO
The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclobutanos/química , Aminoácidos Excitatórios/química , N-Metilaspartato/antagonistas & inibidores , Animais , Compostos Azabicíclicos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclobutanos/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Aminoácidos Excitatórios/metabolismo , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Camundongos , Modelos Químicos , Organofosfonatos , Ácidos Pipecólicos/química , Ácidos Pipecólicos/metabolismo , Piperazinas/química , Piperazinas/metabolismo , RatosRESUMO
In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.
