Asunto(s)
Encéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Serotonina/metabolismo , Transmisión Sináptica/fisiología , Animales , Unión Competitiva/fisiología , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Esquema de Medicación , Masculino , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de Serotonina/efectos de los fármacos , Sulfonamidas/farmacología , Transmisión Sináptica/efectos de los fármacos , Tiofenos/farmacologíaRESUMEN
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Asunto(s)
Antidepresivos Tricíclicos/síntesis química , Encéfalo/efectos de los fármacos , Química Farmacéutica/métodos , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Animales , Antidepresivos Tricíclicos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/química , Humanos , Enlace de Hidrógeno , Microsomas/efectos de los fármacos , Modelos Químicos , Conformación Molecular , Isoformas de Proteínas , Ratas , Antagonistas de la Serotonina/farmacologíaRESUMEN
We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT_{6} receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02 +/- 27.53 pmol/mg prot.) compared to controls (823.33 +/-196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT_{6} receptor density was significantly lower (p< 0.01) in AD (6.67 +/- 0.83) compared to controls (16.67 +/- 3.33). Splitting these results by sex, 5-HT_{6} receptor activation was significantly lower (p< 0.01) in AD females compared to males (121.67 +/- 30.02 vs. 231.67 +/- 34.17 pmol/mg prot). 5-HT_{6} density and 5-HT levels were significantly correlated (p < or = 0.01) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT_{6} activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD.