RESUMEN
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT(6) receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT(6) binding affinity with K(i) values <10nM. Depending on substitution, both agonists (e.g., 6o: EC(50)=60nM, E(max)=70%) and antagonists (6y: IC(50)=17 nM, I(max)=86%) were identified in a 5-HT(6) adenylyl cyclase assay.
Asunto(s)
Indoles/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/química , Sulfonas/química , Humanos , Indoles/síntesis química , Indoles/farmacología , Ligandos , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Asunto(s)
Piridinas/farmacología , Pirroles/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Células HeLa , Humanos , Ligandos , Piridinas/química , Pirroles/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/químicaRESUMEN
A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Animales , Corteza Cerebral/metabolismo , Ácido Glutámico/análisis , Ácido Glutámico/metabolismo , Células HeLa , Humanos , Unión Proteica , Ratas , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/síntesis química , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/metabolismoAsunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Furanos/farmacología , Peptidoglicano/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Bacterias/metabolismo , Furanos/síntesis química , Furanos/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Peptidoglicano/biosíntesisRESUMEN
Pulvinones were synthesized (>180) in arrays and evaluated as inhibitors of early stage cell wall biosynthesis enzymes MurA-MurD. Several pulvinones inhibited Mur enzymes with IC(50)'s in the 1-10 microg/mL range and demonstrated antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphyloccus aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Lactonas/síntesis química , Streptococcus pneumoniae/metabolismo , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Farmacorresistencia Bacteriana , Enterococcus faecalis/metabolismo , Concentración 50 Inhibidora , Meticilina/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Penicilinas/farmacología , Staphylococcus aureus/metabolismo , Vancomicina/farmacologíaRESUMEN
Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which N,N-dimethyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8t and N-methyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8u showed high affinity for 5-HT(6) receptors with K(i)=3.7 and 5.7 nM, respectively.