RESUMEN
To further proceed with our previous work, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate.
Asunto(s)
Amidas/química , Antagonistas de los Receptores Histamínicos/química , Receptores Histamínicos H3/metabolismo , Amidas/farmacología , Animales , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Masculino , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Muscarínicos/química , Solubilidad , Esteroides/químicaRESUMEN
There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Nootrópicos/farmacología , Escopolamina/toxicidad , Animales , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Oxígeno/sangre , Ratas , Ratas Wistar , Especificidad de la EspecieRESUMEN
Objective To study the effects of formaldehyde inhalation on spatial learning abilities and hippocampal neurotransmitters levels of mice, and to explore the neurotoxic mechanism. Methods Three groups of male Kunming mice were exposed to different concentrations (0, 1.34 and 4.02 mg/m3) of gaseity formaldehyde, 4 h/day, for 7 consecutive days,and their behavior when they learned to perform a water labyrinth task and hippocampal neurotransmitters levels were tested. Results There was no significant difference was seen in swimming duration among groups. While on days 5 and 7, mice in group of 4.02 mg/m3 formaldehyde exposure made notable more swimming errors (P