title: Design, Synthesis, and Biological Evaluation of Imidazo[1,5-a]quinoline as Highly Potent Ligands of Central Benzodiazepine Receptors.
abstract: A series of imidazo[1,5-a]quinoline derivatives was designed and synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high CBR affinity with Ki values within the submicromolar and subnanomolar ranges with interesting modulations in their structure-affinity relationships. In particular, fluoroderivative 7w (Ki = 0.44 nM) resulted in the most potent ligand among the imidazo[1,5-a]quinoline derivatives described so far. Overall, these observations confirmed the assumption concerning the presence of a large though apparently saturable lipophilic pocket in the CBR binding site region interacting with positions 4 and 5 of the imidazo[1,5-a]quinoline nucleus. The in vivo biological characterization revealed that compounds 7a,c,d,l,m,q,r,w show anxiolytic and antiamnestic activities without the unpleasant myorelaxant side effects of the classical 1,4-BDZ. Furthermore, the effect of 7l,q,r, and 8i in lowering lactate dehydrogenase (LDH) release induced by ischemia-like conditions in rat brain slices suggested neuroprotective properties for these imidazo[1,5-a]quinoline derivatives.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Castriconi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Grisci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Paolino
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Braile
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Di Capua
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino (NEUROFARBA), Sezione Farmacologia e Tossicologia, Università di Firenze , Viale G. Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino (NEUROFARBA), Sezione Farmacologia e Tossicologia, Università di Firenze , Viale G. Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ricci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena , Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.affiliation: Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Cittadella Universitaria , S.S. 554-Km 4.500, 09042 Monserrato Cagliari, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Mascia
authors.affiliation: Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Cittadella Universitaria , S.S. 554-Km 4.500, 09042 Monserrato Cagliari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
mesh_terms: D000647:Amnesia / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000737:chemistry*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D015195:Drug Design; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D008024:Ligands; D018696:Neuroprotective Agents; D011804:Quinolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines