RESUMEN
A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.
Asunto(s)
Acrilamidas/síntesis química , Cinamatos/síntesis química , Morfolinas/síntesis química , Canales de Potasio/efectos de los fármacos , Acrilamidas/química , Acrilamidas/farmacología , Animales , Cinamatos/química , Cinamatos/farmacología , Depresión de Propagación Cortical/efectos de los fármacos , Humanos , Canal de Potasio KCNQ2 , Ratones , Morfolinas/química , Morfolinas/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Canales de Potasio con Entrada de Voltaje , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.
Asunto(s)
Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Triptaminas/química , Animales , Ciclohexenos/síntesis química , Ciclohexenos/química , Ciclohexenos/farmacología , Fluoxetina/química , Fluoxetina/farmacología , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Microdiálisis , Conformación Molecular , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis químicaRESUMEN
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Asunto(s)
Química Farmacéutica/métodos , Receptores ErbB/antagonistas & inhibidores , Pirroles/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/síntesis química , Adenosina Trifosfato/química , Animales , Células CACO-2 , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Fosfatos/química , Pirroles/farmacología , Ribosa/química , Triazinas/farmacologíaRESUMEN
Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.