RESUMEN
SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and 9.02+/-0.05, respectively and is a potent competitive antagonist (pA(2) 7.85+/-0.04). It displays over 200-fold selectivity for the 5-HT(6) receptor over all other receptors, ion channels and enzymes tested to date. SB-399885 inhibited ex vivo [(125)I]SB-258585 (4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide) binding with an ED(50) of 2.0+/-0.24 mg/kg p.o. in rats. It had a minimum effective dose of 1 mg/kg p.o. in a rat maximal electroshock seizure threshold test and a long duration of action, overall demonstrating an excellent pharmacokinetic-pharmacodynamic correlation. Repeated administration of this agent (10 mg/kg p.o., b.i.d. for 7 days) significantly reversed a scopolamine-induced deficit (0.5 mg/kg i.p.) in a rat novel object recognition paradigm. Moreover, in aged rats (22 months old) SB-399885 (10 mg/kg p.o., b.i.d. for 7 days) fully reversed the age-dependent deficit in water maze spatial learning compared to vehicle-treated age-matched controls and significantly improved recall of the task measured by increases in the searching of the target quadrant on post-training days 1, 3 and 7. In vivo microdialysis in the rat medial prefrontal cortex demonstrated that acute SB-399885 (10 mg/kg p.o.) significantly increased extracellular acetylcholine levels. These data demonstrate that SB-399885 is a potent, selective, brain penetrant, orally active 5-HT(6) receptor antagonist with cognitive enhancing properties that are likely to be mediated by enhancements of cholinergic function. These studies provide further support for the potential therapeutic utility of 5-HT(6) receptor antagonists in disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.
Asunto(s)
Envejecimiento/psicología , Cognición/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Piperazinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Acetilcolina/metabolismo , Animales , Química Encefálica/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Electrochoque , Células HeLa , Humanos , Masculino , Microdiálisis , Piperazinas/farmacocinética , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Convulsiones/prevención & control , Estimulación Química , Sulfonamidas/farmacocinéticaRESUMEN
Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
Asunto(s)
Encéfalo/metabolismo , Piperazinas/síntesis química , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Barrera Hematoencefálica , Perros , Conformación Molecular , Permeabilidad , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solid-phase chemistry resulted in the identification of compounds with high-affinity for the 5-ht5A receptor. The structure-activity relationship within this series and further array synthesis led to the identification of the biphenylmethylamine derivative 11, a potent and selective 5-ht5A receptor antagonist.