title: New 3-, 8-disubstituted pyrazolo[5,1-c][1,2,4]benzotriazines useful for studying the interaction with the HBp-3 area (hydrogen bond point area) in the benzodiazepine site on the γ-aminobutyric acid type A (GABAA) receptor.
abstract: The pharmacophoric model using ADLR procedure, based on pyrazolo[5,1-c][1,2,4]benzotriazine system, studied in our laboratory, allowed us to identify the essential interaction points (HBp-1, HBp-2, and Lp-1) and the important areas for affinity modulation (HBp-3 and Lp-2) for binding recognition at benzodiazepine (Bzs) site of GABA(A) receptors (GABA(A)-Rs). In this work ADLR method is used to rationalize the affinity data of 23 new compounds and to improve the knowledge on HBp-3 area, hydrogen bond area. Among these new compounds emerge the pyrrolo derivatives (18, 25, 28, 34, and 37) for their good affinity value (14.9>K(i)(nM)>63.0). In the orientations proposed by ADLR, the NH moiety of the pyrrole ring, independently of the position in the pyrazolobenzotriazine core, fits in HBp-3 area and points out the acceptor feature of this hydrogen bond area, already known as donor area. Unexpectedly, the oxygen atom of the furane ring does not form efficient hydrogen bond with the same area, probably for an imperfect distance. The size of substituent at position 8 is important but not necessary for the receptor recognition, in fact the interdependence between the features of the 3- and 8-substituent's is again verified, (i.e., compound 20 vs 32).
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente attivi Università degli Studi di Firenze, 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: 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: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Annarella
authors.initials: A
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011720:Pyrazoles; D011963:Receptors, GABA-A; D014227:Triazines