RESUMO
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
Assuntos
Atenção/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Indanos/farmacologia , Memória/efeitos dos fármacos , Oxazóis/farmacologia , Pirimidinas/farmacologia , Receptores de AMPA/química , Esquizofrenia/tratamento farmacológico , Sítio Alostérico , Anfetaminas/farmacologia , Animais , Cálcio/metabolismo , Córtex Cerebral/metabolismo , AMP Cíclico/metabolismo , Maleato de Dizocilpina/química , Maleato de Dizocilpina/farmacologia , Eletroconvulsoterapia , Células HEK293 , Humanos , Indanos/uso terapêutico , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxazóis/uso terapêutico , Fenótipo , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
Assuntos
Anilidas/síntese química , Anilidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Divisão Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologiaRESUMO
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 microM) against T-cell proliferation.
