RESUMO
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.
Assuntos
Antidepressivos Tricíclicos/síntese química , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Receptores de Serotonina/química , Antagonistas da Serotonina/síntese química , Animais , Antidepressivos Tricíclicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/química , Humanos , Ligação de Hidrogênio , Microssomos/efeitos dos fármacos , Modelos Químicos , Conformação Molecular , Isoformas de Proteínas , Ratos , Antagonistas da Serotonina/farmacologiaRESUMO
The objective of this study was to establish the optimal blood concentrations of the potent P-glycoprotein (P-gp) inhibitor GF120918 (Elacridar) required to achieve maximal knockout of this efflux transporter in the blood-brain barrier (BBB) of mice, rats, and guinea pigs. Genetic mdr1a/b(-/-) knockout mice and "chemical" P-gp knockout mice, rats, and guinea pigs, generated by 24 h continuous infusion of GF120918, were used to investigate the effects of P-gp modulation on the brain penetration of SB-487946. Genetic mdr1a/b(-/-) knockout mice demonstrated a >70-fold increase in brain:blood ratio of SB-487946 compared to mdr1a/b(+/+) wild-type mice. There was a similar increase in SB-487946 brain:blood ratio in GF120918-treated mice (ca. >67-fold) and rats (ca. 95-fold) but a significantly smaller increase (ca. 10-fold) in guinea pigs treated with GF120918. An appreciable difference was found in the BBB functional effect of P-gp efflux in rodents. GF120918 blood EC90 in mice and rats were similar however, the EC90 in guinea pigs was ca. 10-fold higher, suggesting a species difference in the activity of P-gp at the BBB in some rodents. This study establishes the optimal blood concentrations of GF120918 in relation to SB-487946, to achieve chemically induced P-gp knockout in rodents.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Barreira Hematoencefálica/fisiologia , Acridinas/farmacocinética , Animais , Animais Geneticamente Modificados , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Genes MDR/genética , Cobaias , Masculino , Espectrometria de Massas , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Tetra-Hidroisoquinolinas/farmacocinéticaRESUMO
1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.
Assuntos
Fenóis/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacocinética , Serotonina/análogos & derivados , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Animais , Células CHO , Linhagem Celular , Membrana Celular/fisiologia , Cricetinae , AMP Cíclico/metabolismo , Vias de Administração de Medicamentos , Regulação da Expressão Gênica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Humanos , Hipotermia/induzido quimicamente , Fenóis/administração & dosagem , Pirrolidinas/administração & dosagem , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética , Serotonina/administração & dosagem , Serotonina/farmacocinética , Serotonina/farmacologia , Serotonina/fisiologia , Antagonistas da Serotonina/administração & dosagem , TrítioRESUMO
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.