RESUMO
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Assuntos
Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Tiazóis/química , Triptaminas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Lobo Frontal/metabolismo , Haplorrinos , Humanos , Técnicas In Vitro , Camundongos , Microdiálise , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Solubilidade , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triptaminas/química , Triptaminas/farmacocinética , Triptaminas/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Several series of conformationally constrained N1-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT6 receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8-13) appear to be able to adopt a conformation that allows high affinity 5-HT6 receptor binding, while the beta-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC50 = 24 nM. Several of the N1-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC50 = 0.8, 1.0 nM).
Assuntos
Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Agonistas do Receptor de Serotonina/síntese química , Triptaminas/síntese química , Adenilil Ciclases/metabolismo , AMP Cíclico/biossíntese , Humanos , Conformação Molecular , Ligação Proteica , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.
Assuntos
Indóis/síntese química , Pirrolidinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Sulfonamidas/síntese química , AMP Cíclico/agonistas , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Células HeLa , Humanos , Indóis/química , Indóis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A series of N(1)-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)indole derivatives was designed and synthesized. These compounds were shown to have high affinity for the 5-HT(6) receptor. Two analogs, 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-1-sulfonyl]-phenylamine 15g and 4-[3-(1,2,3,6-tetrahydropyridin-4-yl)-5-methoxy-1H-indole-1-sulfonyl]-phenylamine 15y, had 0.4 and 3.0 nM affinity, respectively, and antagonized the production of adenylate cyclase at sub-nanomolar concentrations.
