CNR ExploRA

Articolo in rivista, 2019, ENG, 10.3390/ijms20061438

Synthesis of New GABA(A) Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold

Guerrini, G.; Vergelli, C.; Cantini, N.; Giovannoni, M. P.; Daniele, S.; Mascia, M. P.; Martini, Cl.; Crocetti, L.

1, 2, 3, 4, 8: Dipartimento Neurofarba, sezione Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, Firenze, 50019, Italy; 5, 7: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, Pisa, 56126, Italy; 6: CNR--Institute of Neuroscience, Cittadella Universitaria, Monserrato, Cagliari 09042, Italy

We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the -aminobutyric type A (GABA(A)) subtype receptor. Continuing the study in this field, we report here the design and synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline 8-methoxy substituted as interesting analogs of the above (hetero)arylalkylester, in which the shortening or the removal of the linker between the 3-(hetero)aryl ring and the PQ was performed. Only compounds that are able to inhibit radioligand binding by more than 80% at 10 M have been selected for electrophysiological studies on recombinant 122L GABA(A) receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABA(A)R in an opposite manner, since 6b enhances and 6a reduces the variation of the chlorine current, suggesting that they act as a partial agonist and an inverse partial agonist, respectively. The most potent derivative was 3-(4-methoxyphenylcarbonyl)-8-methoxy-4,5-dihydropyrazolo[1,5-a] quinazoline 11d, which reaches a maximal activity at 1 M (+54%), and it enhances the chlorine current at 0.01 M. Finally, compound 6g, acting as a null modulator at 122L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new +/- non-traditional' benzodiazepine site.

International journal of molecular sciences (Online) 20 (6)