Paper Citing NAMD - Abstract
Anzini, Maurizio; Valenti, Salvatore; Braile, Carlo; Cappelli, Andrea; Vomero, Salvatore; Acaro, Stefano; Ortuso, Francesco; Marinelli, Luciana; Limongelli, Vittorio; Novellino, Ettore; Betti, Laura; Giannaccini, Gino; Lucacchini, Antonio; Daniele, Simona; Martini, Claudia; Ghelardini, Carla; Mannelli, Lorenzo Di Cesare; Giorgi, Gianluca; Mascia, Maria Paola; Biggio, Giovanni
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
JOURNAL OF MEDICINAL CHEMISTRY, 54:5694-5711, AUG 25 2011
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.
