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

Abstract

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.

4,5-Dihydro-5-Oxo-Pyrazolo[1,5-a]Thieno[2,3-c]Pyrimidine: A Novel Scaffold Containing Thiophene Ring. Chemical Reactivity and In Silico Studies to Predict the Profile to GABAA Receptor Subtype

“… Finally, the alkylation of 7 and 8 in the usual manner afforded a mixture of the N-methyl and O-methyl derivatives ( 12e and 13e ; 12f and 13f ), which were separated by flash chromatography. The assignment of the exact structure was carried out with the use of 1 H-NMR technique, whose results are in agreement with our previous data [ 8 ]: when methyl is bound to N-4, the peak falls between 3.33 and 4.00 ppm, depending on the substituent at 3-position, while the O-methyl is unchanged for all compounds at 4.20 ppm. …”

“…On the six final designed compounds ( 12c – f and 22a , b ), a molecular docking study and an evaluation of the ‘Proximity Frequencies’ [ 8 , 13 ] were performed to predict their profile on the α1β2γ2-GABA A R subtype.…”

“…Starting from these evidences, we addressed our research towards the synthesis of heterocyclic compounds containing the thiophene ring. We applied this strategy to the synthesis of potential GABA A R subtypes ligands, which represent a field of research extensively investigated by us for many years, by obtaining some interesting derivatives with pyrazolobenzotriazine, pyrazolopyrimidine and pirazoloquinazoline scaffold [ 5 , 6 , 7 , 8 ]. This choice is also supported by the fact that in the literature are present some GABA A R ligands (Ro 19-4603, TB21007, Comp.…”

“…16), in which the thiophene ring is fused or bonded to other cycles ( Figure 2 ) [ 9 , 10 , 11 ]. In particular, we report here the synthesis of new compounds with 4,5-dihydro-5-oxo-pyrazolo[1,5-a]thieno[2,3-c]pyrimidine and pyrazolo[1,5-a]thieno[2,3-c]pyrimidine scaffold as result of the isosteric replacement of the benzene with thiophene ring in our pyrazolo[1,5-a]quinazolines previously published as GABA A R subtype ligands [ 8 , 12 ] ( Figure 3 ). Moreover, these new compounds can be considered as analogues of the abovementioned GABA A R ligand Ro 19-4603, in which we formally operated a contraction of the central diazepine ring.…”

“…Thus, it was very intriguing to investigate the feasibility and the reactivity of this nucleus toward the most common reactions, such as alkylation, reduction, halogenation, and hydrolysis. Finally, molecular docking studies and evaluation of the ‘Proximity Frequencies’ (exploiting our reported model) [ 8 , 13 ] were performed on all the final compounds to predict their profile on the α1β2γ2-GABAAR subtype.…”