Asunto(s)
Compuestos Aza/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Compuestos de Espiro/farmacología , Compuestos Aza/química , Línea Celular , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Estructura Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Compuestos de Espiro/químicaRESUMEN
The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
Asunto(s)
Benzazepinas/síntesis química , Benzazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzazepinas/química , Técnicas Químicas Combinatorias , Antagonistas de Dopamina/química , Diseño de Fármacos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.