Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity.
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.
Ferlin
Maria Grazia
MG
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Padova, Via Marzolo 5, 35131 Padova, Italy. mariagrazia.ferlin@unipd.it
Chiarelotto
Gianfranco
G
Dall'Acqua
Stefano
S
Maciocco
Elisabetta
E
Mascia
Maria Paola
MP
Pisu
Maria Giuseppina
MG
Biggio
Giovanni
G
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
D018757:GABA Modulators; D007546:Isoquinolines; D011720:Pyrazoles; D015363:Quinolones; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005445:Flunitrazepam; C037850:PK 11195