title: Novel 3-aroylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted, ligands at GABAA/benzodiazepine receptor complex: synthesis, pharmacological and molecular modeling studies.
abstract: The synthesis and binding studies of a series of 3-acylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted are reported. High-affinity ligands at benzodiazepine site on GABA(A) receptor complex (GABA(A)/BzR complex) were obtained when the 3-aroyl substituent is represented by a five-member heteroaroyl ring (furoyl-, thenoyl-, and pyrroyl-). Moreover the type of heteroaroyl ring at position 3 influences the feature of the substituent at position 8 to obtain high-affinity ligands: a 'hydrogen-bond acceptor ring' at position 3 is synergic with an electron donor substituent at position 8, while a 'hydrogen-bond donor ring' is synergic with a withdrawing substituent. Compounds 8a, 9b, and 11 were deeply studied in vivo for their pharmacological effects considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motor activity and explorative activity, anxiolytic-like effects, mouse learning and memory modulation, and ethanol-potentiating action. To rationalize and qualitatively interpret the GABA(A)/Bz binding affinities of compounds 8a and 11, a dynamic molecular modeling study has been performed, with the aim of assessing the preferred geometry of protein-ligand complex.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente attivi (HeteroBioLab) Università degli Studi di Firenze, Via U. Schiff, 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: Fabrizio
authors.initials: F
authors.lastname: Melani
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: Monica
authors.initials: M
authors.lastname: Norcini
authors.forename: Annarella
authors.initials: A
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010087:Oxides / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D008024:Ligands; D010087:Oxides; D011720:Pyrazoles; D011963:Receptors, GABA-A; D014227:Triazines; D000431:Ethanol; C031280:pyrazole