RESUMO
The synthesis and biological activity are reported for a series of analogues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT(2C) receptor binding site. Small molecule modeling studies have been used to define a region in space which is allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor. In a complementary approach, docking of 2 into our model of the 5-HT(2C) receptor has allowed us to propose a novel primary binding interaction for this series of diaryl ureas, involving a potential double hydrogen-bonding interaction between the urea carbonyl oxygen of the ligand and two serine residues in the receptor. The difference of two valine residues in the 5-HT(2C) receptor for leucine residues in the 5-HT(2A) receptor is believed to account for the observed 5-HT(2C)/5-HT(2A) selectivity with 2.
Assuntos
Antagonistas da Serotonina/síntese química , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Técnicas In Vitro , Indóis/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Piridinas/química , Ensaio Radioligante , Ratos , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologiaRESUMO
The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.
Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Indóis/síntese química , Piridinas/síntese química , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Linhagem Celular , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Modelos Moleculares , Atividade Motora/efeitos dos fármacos , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT2A de Serotonina , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.
Assuntos
Ansiolíticos , Indóis , Modelos Moleculares , Piridinas , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Conflito Psicológico , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Comportamento Social , Relação Estrutura-AtividadeAssuntos
Fenóis/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Sulfonamidas/síntese química , Linhagem Celular , Humanos , Modelos Moleculares , Fenóis/química , Fenóis/metabolismo , Ensaio Radioligante , Receptores de Serotonina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.
Assuntos
Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Animais , Humanos , Técnicas In Vitro , Cinética , Espectroscopia de Ressonância Magnética , Modelos Químicos , Compostos de Fenilureia/síntese química , Piridinas/síntese química , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
Bisaryl ethers have been identified with excellent 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their potential as novel non-sedating anxiolytic and antidepressants is under investigation.