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Int J Mol Sci
2022 Oct 27;2321:. doi: 10.3390/ijms232113032.
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GABAA Receptor Modulators with a Pyrazolo[1,5-a]quinazoline Core: Synthesis, Molecular Modelling Studies and Electrophysiological Assays.
Crocetti L
,
Guerrini G
,
Melani F
,
Vergelli C
,
Mascia MP
,
Giovannoni MP
.
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As a continuation of our study in the GABAA 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 α1β2γ2-GABAAR 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 µM) on the modulation of GABAA receptor function through electrophysiological techniques on recombinant α1β2γ2L-GABAA 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 GABAA receptor modulators.
Figure 6. Concentration-response curves of compounds 3, 4, 6a, b, 8, 9, 12a–c, 13a (panel (a,b)) and 15, 17–19 (panel (c)) on GABA-induced Cl− currents in Xenopus laevis oocytes expressing recombinant α1β2γ2L-GABAA receptors. Data are expressed as the percentage modulation of the response induced by GABA at EC5-10 values (approximatively 3–5 μM) and are the mean ± SEM of values obtained from two to nine oocytes.* p < 0.05; ** p < 0.01.
Figure 7. Compound 3 antagonized the potentiation of GABA-induced Cl− currents by lorazepam in Xenopus laevis oocytes expressing recombinant α1β2γ2L-GABAA receptors. Data are expressed as the percentage modulation of the response induced by GABA at EC5-10 values (approximatively 3–5 μM) and are the mean ± SEM of values obtained from four oocytes.
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