title: Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity.
abstract: A series of pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives 6, 7a-c, 8a,b, 9a,b and 10-12 were synthesized as modified pyrazoloquinolinone analogs (PQs) and evaluated for their ability to inhibit radioligand to central and peripheral benzodiazepine receptors (BZRs) and their effect on GABA(A) alpha1beta2gamma2L receptors expressed in Xenopus laevis oocytes. Multistep synthesis starting from 5-nitroindole, via the Gould-Jacobs reaction to the quinoline nucleus, yielded key intermediates 9-chloro-3H-pyrrolo[3,2-f]quinoline-8-carboxylates. The reaction of the latter with methyl-hydrazine and various phenyl-hydrazines furnished the final compounds. In order to confirm the expected tetracyclic 2-substituted-2H-pyrazolopyrroloquinolin-3-one structure, IR spectrophotometric, mono-1H and 13C and bi-dimensional spectrometric and HRMS analyses were carried out: all compounds were found to be 2-substituted 3-keto tautomers; compound 6 only differed because it turned out to be 1-methyl-2H-pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-olo. The results of this work are consistent with those previously reported for PQs: 7-9 show high potency in displacing specific [3H]flunitrazepam from its receptor site; no compound was active in inhibiting the binding of [3H]PK 11195. They all act as antagonists at central BZR.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Padova, Via Marzolo 5, 35131 Padova, Italy. mariagrazia.ferlin@unipd.it
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ferlin
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Chiarelotto
authors.forename: Stefano
authors.initials: S
authors.lastname: Dall'Acqua
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Maciocco
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Mascia
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Pisu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D018757:GABA Modulators; D007546:Isoquinolines; D011720:Pyrazoles; D015363:Quinolones; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005445:Flunitrazepam; C037850:PK 11195