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
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2D6 , Avaliação Pré-Clínica de Medicamentos , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Técnicas In Vitro , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.