title: 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.
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 (36)Cl(-) in rat cerebrocortical 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 anxiolytic 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 α(1)β(2)γ(2)L, α(2)β(1)γ(2)L, and α(5)β(2)γ(2)L 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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. anzini@unisi.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.forename: Carlo
authors.initials: C
authors.lastname: Braile
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Mascia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002417:Cattle; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000493:pharmacokinetics; D005442:Flumazenil / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium; D014982:Xenopus laevis
chemical_list: D002712:Chlorides; D008024:Ligands; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D005442:Flumazenil