GABA(A) Receptor Modulators with a Pyrazolo[1,5-a]quinazoline Core: Synthesis, Molecular Modelling Studies and Electrophysiological Assays

As a continuation of our study in the GABA(A) receptor modulators field, we report the design and synthesis of new 8-chloropyrazolo[1,5-a]quinazoline derivatives. Molecular docking studies and the evaluation of the 'Proximity Frequencies' (exploiting our reported model) were performed on all the final compounds (3, 4, 6a-c, 7a,b, 8, 9, 12a-c, 13a,b, 14-19) to predict their profile on the alpha 1 beta 2 gamma 2-GABA(A)R subtype. Furthermore, to verify whether the information coming from this virtual model was valid and, at the same time, to complete the study on this series, we evaluated the effects of compounds (1-100 mu M) on the modulation of GABA(A) receptor function through electrophysiological techniques on recombinant alpha 1 beta 2 gamma 2L-GABA(A) receptors expressed in Xenopus laevis oocytes. The matching between the virtual prediction and the electrophysiological tests makes our model a useful tool for the study of GABA(A) receptor modulators.