3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K-i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of Cl-36(-) in rat cerebrocottical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe arudolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant alpha(1)beta(2)gamma L-2, alpha(2)beta(1)gamma L-2, and alpha(5)beta(2)gamma L-2 human GABA(A) receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer's GABA(A) homology model.
New Insight into the Central Benzodiazepine Receptor-Ligand Interactions: Design, Synthesis, Biological Evaluation, and Molecular Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds
Mascia Maria Paola;
2011
Abstract
3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K-i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of Cl-36(-) in rat cerebrocottical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe arudolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant alpha(1)beta(2)gamma L-2, alpha(2)beta(1)gamma L-2, and alpha(5)beta(2)gamma L-2 human GABA(A) receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer's GABA(A) homology model.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
