RESUMEN
A comparison between compounds with pyrazolo[1,5-a]pyrimidine structure (series 4-6) and pyrazolo[5,1-c][1,2,4]triazine core (series 9) as ligands at GABAA-receptor subtype, was evaluated. Moreover, for pyrazolotriazine derivatives having binding recognition, the interaction on recombinant rat α(1-3,5) GABAA receptor subtypes, was performed. Among these latter, emerge compounds 9c, 9k, 9l, 9m and 9n as α1-selective and 9h as α2-selective ligands.
Asunto(s)
Pirazoles/farmacología , Receptores de GABA-A/metabolismo , Triazinas/farmacología , Animales , Sitios de Unión , Bovinos , Membrana Celular/metabolismo , Corteza Cerebral/metabolismo , Flumazenil/química , Ligandos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Ratas , Receptores de GABA-A/química , Triazinas/síntesis química , Triazinas/química , TritioRESUMEN
In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells. Compound 4 displayed affinity only for alpha1beta2gamma2 subtype (K(i) = 31 nM), and in an in-depth, in vivo study it revealed sedative and anxiolytic-like properties without any amnesic and myorelaxant effects in rodents.
Asunto(s)
Ansiolíticos/síntesis química , Agonistas de Receptores de GABA-A , Hipnóticos y Sedantes/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Reacción de Prevención/efectos de los fármacos , Unión Competitiva , Encéfalo/metabolismo , Bovinos , Línea Celular , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Técnicas In Vitro , Ratones , Relajación Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A , Proteínas Recombinantes/metabolismoRESUMEN
The synthesis and binding study of new 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 3-ester compounds are reported. A pharmacological evaluation of the high-affinity ligands 1-4 belonging to the 3-heteroarylester series is made. The 3-(2-thienylmethoxycarbonyl) derivative 4 stands out from the other heteroarylesters and is found, using nine different behavioral methods, to be a functionally selective ligand in vivo: it shows anxiolytic-like activity in the conflict models (light-dark box and plus maze test) similarly to diazepam, without any sedative and amnesic properties or interference from alcohol.
Asunto(s)
Ansiolíticos/síntesis química , Óxidos N-Cíclicos/síntesis química , GABAérgicos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Receptores de GABA-A/efectos de los fármacos , Triazinas , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Reacción de Prevención/efectos de los fármacos , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacología , Interacciones Farmacológicas , Etanol/farmacología , Conducta Exploratoria/efectos de los fármacos , GABAérgicos/química , GABAérgicos/farmacología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Técnicas In Vitro , Ligandos , Memoria/efectos de los fármacos , Ratones , Destreza Motora/efectos de los fármacos , Fármacos Neuromusculares/síntesis química , Fármacos Neuromusculares/química , Fármacos Neuromusculares/farmacología , Ratas , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Sueño/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.
Asunto(s)
Pirimidinas/síntesis química , Receptores de GABA-A/efectos de los fármacos , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacología , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Unión Competitiva , Encéfalo/metabolismo , Bovinos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Relajantes Musculares Centrales/síntesis química , Relajantes Musculares Centrales/química , Relajantes Musculares Centrales/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad Cuantitativa , Receptores de GABA-A/metabolismoRESUMEN
Reaction of 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidine 1 with 1,3- and 1,4-bisnucleophiles has been investigated; obtainment of new polycyclic heterocyclic derivatives is reported. A convenient procedure leading to new pyrazolo[1,5-a]quinazolines is described; a modest bioactivity of these compounds against two human tumor cell lines was also ascertained.
Asunto(s)
Pirimidinas/química , Pirimidinas/síntesis química , Proliferación Celular/efectos de los fármacos , Electrones , Humanos , Células Jurkat , Compuestos Policíclicos/síntesis química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and the binding study of new 3-arylesters and 3-heteroarylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 8-substituted are reported. The nature of these substituents (in terms of lipophilic and electronic features) seems to influence the binding affinity. High-affinity ligands were studied in mice in vivo for their pharmacological effects, considering six potential benzodiazepine actions: anxiolytic-like effects, muscle relaxant effects, motor coordination, anticonvulsant action, spontaneous motor activity, and ethanol-potentiating action. Compounds 4d and 6d showed an inverse-agonist profile. These compounds were evaluated also for their binding at benzodiazepine site on GABAA receptor complex (GABAA/BzR complex) subtype to evaluate their subtype selectivity.
Asunto(s)
Agonistas de Receptores de GABA-A , Receptores de GABA-A/metabolismo , Triazinas/síntesis química , Triazinas/farmacología , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacología , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Ansiedad/tratamiento farmacológico , Unión Competitiva , Encéfalo/metabolismo , Bovinos , Flumazenil/metabolismo , Técnicas In Vitro , Ligandos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Ratas , Ratas Wistar , Sueño/efectos de los fármacos , Relación Estructura-Actividad , Triazinas/química , Triazinas/metabolismoRESUMEN
The present paper reports the synthesis and binding studies of new 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as selective Peripheral Benzodiazepine Receptor (PBR) ligands. The variability of substituents at the 3-position was investigated and a 3D-QSAR model was proposed to evaluate the effect of different substitutions on the acetamide moiety. In addition, a subset of the novel compounds showing high affinity for PBR was tested for their ability to modulate the steroid biosynthesis in C6 glioma cells.