RESUMO
Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Quinolinas/síntese química , Receptores da Neurocinina-3/antagonistas & inibidores , Aminas/metabolismo , Animais , Área Sob a Curva , Encéfalo/metabolismo , Córtex Cerebral/embriologia , Gerbillinae , Masculino , Modelos Químicos , Quinolinas/metabolismo , Quinolinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.
Assuntos
Química Farmacêutica/métodos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Administração Oral , Animais , Cromatografia/métodos , Desenho de Fármacos , Humanos , Cinética , Masculino , Modelos Químicos , Conformação Molecular , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134) potently inhibited [125I]SB-258585 and [3H]LSD binding in a HeLa cell line expressing human 5-HT(6) receptors (pK(i)=8.6 and 8.54, respectively). Furthermore, SB-357134 inhibited [125I]SB-258585 binding in human caudate--putamen and in rat and pig striatum membranes (pK(i)=8.82, 8.44, and 8.61, respectively). SB-357134 displayed over 200-fold selectivity for the 5-HT(6) receptor versus 72 other receptors and enzymes. 5-HT-stimulated cyclic AMP (cAMP) accumulation in human 5-HT(6) receptors was competitively antagonised by SB-357134 (pA(2)=7.63). SB-357134 inhibited ex vivo [125I]SB-258585 binding in the rat with an ED(50) of 4.9 +/- 1.3 mg/kg po, 4 h postdose. In the rat maximal electroshock seizure threshold (MEST) test, SB-357134 produced a potent and dose-dependent increase in seizure threshold, with a minimum effective dose of 0.1 mg/kg po. At 10 mg/kg po, maximum activity occurred between 4 and 6 h postdose. Good exposure was observed with SB-357134 at 10 mg/kg po, reaching maximal blood and brain concentrations of 4.3 +/- 0.2 and 1.3 +/- 0.06 microM, respectively, 1 h postdose. In addition, SB-357134 (10 mg/kg po) enhanced memory and learning following chronic administration (twice a day for 7 days) in the rat water maze. Overall, these studies demonstrate that SB-357134 is a potent, selective, brain penetrant, and orally active 5-HT(6) receptor antagonist.
Assuntos
Encéfalo/metabolismo , Piperazinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Algoritmos , Animais , Química Encefálica/efeitos dos fármacos , Cognição/efeitos dos fármacos , AMP Cíclico/metabolismo , Eletrochoque , Comportamento Exploratório/efeitos dos fármacos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Membranas/efeitos dos fármacos , Membranas/metabolismo , Piperazinas/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Proteínas Recombinantes/efeitos dos fármacos , Convulsões/prevenção & controle , Antagonistas da Serotonina/metabolismo , Sulfonamidas/metabolismo , SuínosRESUMO
The synthesis of novel 3-(octahydropyrido[1,2-a]pyrazin-2-yl)- and 3-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)phenyl-2-benzo[b]thiophene sulphonamide derivatives 3, (S)-4 and (R)-4 is described. The compounds show high affinity for the 5-HT6 receptor, excellent selectivity against a range of other receptors and good brain penetration.