Synthesis, in vivo evaluation, and molecular modeling studies of new pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide derivatives. Identification of a bifunctional hydrogen bond area related to the inverse agonism.
A new series of pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 8-alkyloxy-/aryloxy-/arylalkyloxy and 8-aryl-/arylalkylderivatives variously substituted at the 3-position were synthesized and binding studies at the benzodiazepine site on GABA(A) receptor were carried out. The pharmacological profile was identified for compounds 10, 11, 16(+), 16(-), and 17 by considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motility and explorative activity, potential anxiolytic-like effects, mouse learning and memory modulation, and finally, ethanol-potentiating action. Compound 17 stands out as the compound that improves mouse memory processes selectively, safely, and in a statistically significant manner. From a ligand-based pharmacophoric model, we identified a hydrogen bond interaction area HBp-3 near the lipophilic area. This new pharmacophoric model allowed us to identify four structural compound typologies and thus to rationalize the affinity data of all compounds.
Guerrini
Gabriella
G
Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente attivi (HeteroBioLab), Università degli Studi di Firenze, Via U. Schiff 6, 50019 Polo Scientifico, Sesto Fiorentino-Firenze, Italy. gabriella.guerrini@unifi.it
Ciciani
Giovanna
G
Cambi
Giovanni
G
Bruni
Fabrizio
F
Selleri
Silvia
S
Guarino
Chiara
C
Melani
Fabrizio
F
Montali
Marina
M
Martini
Claudia
C
Ghelardini
Carla
C
Norcini
Monica
M
Costanzo
Annarella
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D002417:Cattle; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006860:Hydrogen Bonding; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D014227:Triazines