RESUMO
Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 9-11) of the pyrazolo[1,5-a]pyrimidine acetamide class, all of which showed high binding affinity and selectivity for the TSPO and, in the case of the propyl, propargyl, and butyl ether derivatives, the ability to increase pregnenolone biosynthesis by 80-175% over baseline in rat C6 glioma cells. While these compounds fit our in silico generated pharmacophore for TSPO binding the current model does not account for the observed functional activity.
Assuntos
Acetamidas/química , Proteínas de Transporte/antagonistas & inibidores , Éteres/química , Pirazóis/química , Piridinas/química , Acetamidas/síntese química , Acetamidas/farmacologia , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Éteres/síntese química , Éteres/farmacologia , Ligantes , Pregnenolona/biossíntese , Ligação Proteica , Ratos , Receptores de GABA-A/metabolismoRESUMO
In the title compound, C(20)H(22)FNO, the distances close to the carbonyl and amine are: N-O = 3.232â (4)â Å and N-C = 2.666â (5)â Å. The crystal packing is unremarkable.
RESUMO
We show that changing the number and position of nitrogen atoms in the heteroatomic core of a pyrazolopyrimidine acetamide is sufficient to induce complex binding to wild type human TSPO. Only compounds with this complex binding profile lacked intrinsic effect on glioblastoma proliferation but positively modulated the antiproliferative effects of a synthetic TSPO ligand. To the best of our knowledge this is the first demonstration of allosteric-like interaction at the wild type human TSPO.