RESUMEN
Since it was known that 5HT properties (5HT1A agonism or 5HT2A antagonism) combined with D2 antagonism may lead to atypical antipsychotic drugs, a series of 19 benzothiazolin-2-one and benzoxazin-3-one derivatives possessing the arylpiperazine moiety was prepared, and their binding profiles were investigated. All tested compounds displayed very high affinities for the 5HT1A and D2 receptors. Therefore, further pharmacological studies were carried out on selected compounds (24, 27, 30, 46, and 47). This evaluation in rats clearly revealed potent antipsychotic properties along with a decrease of extrapyramidal side effects. These derivatives are currently under preclinical development.
Asunto(s)
Antipsicóticos , Oxazinas , Piperazinas , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Tiazoles , Animales , Antipsicóticos/síntesis química , Antipsicóticos/química , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Catalepsia/inducido químicamente , Bovinos , Cuerpo Estriado/metabolismo , Dopaminérgicos/síntesis química , Dopaminérgicos/química , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacología , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Hipercinesia/tratamiento farmacológico , Ratones , Oxazinas/síntesis química , Oxazinas/química , Oxazinas/metabolismo , Oxazinas/farmacología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Conejos , Ratas , Ratas Wistar , Receptores de Serotonina 5-HT1 , Serotoninérgicos/síntesis química , Serotoninérgicos/química , Serotoninérgicos/metabolismo , Serotoninérgicos/farmacología , Sueño/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-Actividad , Porcinos , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.