RESUMO
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.
Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Transtornos Mentais/fisiopatologia , Transtornos Psicóticos/fisiopatologia , Receptores de Serotonina/fisiologia , Adenilil Ciclases/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Encéfalo/patologia , AMP Cíclico/metabolismo , Feminino , Humanos , Masculino , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Transtornos Psicóticos/patologia , Serotonina/metabolismo , Fatores Sexuais , Lobo Temporal/patologia , Lobo Temporal/fisiopatologiaRESUMO
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.