title: Novel 3-iodo-8-ethoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide as promising lead for design of alpha5-inverse agonist useful tools for therapy of mnemonic damage.
abstract: The synthesis and the binding study of new 3-iodiopyrazolo[5,1-c][1,2,4] benzotriazine 5-oxides 8-alkyloxy substituted are reported. The replacement at position 3 with an iodine atom, with respect to substituents capable to form a three centered hydrogen bond and/or to form pi-pi stacking interaction with receptor protein, gave high affinity ligands, independently of the 8-alkyloxy substituent. High-affinity ligands were studied in mice in vivo for their pharmacological effects, considering five potential benzodiazepine actions: anxiolytic-like effects, motor coordination, anticonvulsant action, mouse learning and memory impairment, and ethanol-potentiating action. Compounds 5c and 5'c have an inverse agonist profile and for the first time is evidenced a pro-mnemonic activity. These compounds were evaluated also for their binding at Benzodiazepine site on GABA(A) receptor complex (GABA(A)/BzR complex) subtype to evaluate their subtype selectivity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via U. Schiff, 6, 50019 Polo Scientifico, Sesto Fiorentino (Firenze), Italy. gabriella.guerrini@unifi.it
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guerrini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ciciani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cambi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bruni
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.forename: François
authors.initials: F
authors.lastname: Besnard
authors.forename: Marina
authors.initials: M
authors.lastname: Montali
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.forename: Annarella
authors.initials: A
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001259:Ataxia / Q000139:chemically induced / Q000523:psychology; D003975:Diazepam / Q000494:pharmacology; D015195:Drug Design; D018755:GABA Agonists / Q000494:pharmacology; D018737:Hand Strength; D007202:Indicators and Reagents; D007858:Learning / Q000187:drug effects; D008024:Ligands; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012890:Sleep / Q000187:drug effects; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C519906:3-iodo-8-ethoxypyrazolo(5,1-c)(1,2,4)benzotriazine 5-oxide; D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D007202:Indicators and Reagents; D008024:Ligands; D018697:Nootropic Agents; D011720:Pyrazoles; D011963:Receptors, GABA-A; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D003975:Diazepam