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Int J Mol Sci
2019 Mar 21;206:. doi: 10.3390/ijms20061438.
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Synthesis of New GABAA Receptor Modulator with Pyrazolo[1,5-a]quinazoline (PQ) Scaffold.
Guerrini G, Vergelli C, Cantini N, Giovannoni MP, Daniele S, Mascia MP, Martini C, Crocetti L.
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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 γ-aminobutyric type A (GABAA) 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 μM have been selected for electrophysiological studies on recombinant α1β2γ2L GABAA receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABAAR 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 μM (+54%), and it enhances the chlorine current at ≥0.01 μM. Finally, compound 6g, acting as a null modulator at α1β2γ2L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new α+/β- 'non-traditional' benzodiazepine site.
Figure 1. Panel (A): γ-aminobutyric type A (GABAA) receptor subtype ligands with chemical structures strictly related to the new pyrazoloquinazoline (PQ). Panel (B): general structure of new synthesized PQ compounds. Blue circle 3-aroylpyrazolopyrimidine moiety; Red circle 3-arylpyrazolopyrimidina moiety.
Scheme 1. Synthesis of pyrazolo[1,5-a]quinazolin-4(5H)-ones and pyrazolo[1,5-a]quinazolines bearing an aryl/heteroaryl ring or aroyl/heteroaroyl group at position 3. Reagents and conditions: (i) AcOH or dimethylformamide (DMF)/AcONa; (ii) anhydrous THF and LiAlH4/THF then air; (iii) POCl3/PCl5,N,N-diisopropylethylamine (DIPEA); (iv) EtOH, HCOONH4, Pd/C 10%.
Scheme 2. Synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline. Reagents and conditions: (i) anhydrous THF and LiAlH4/THF; then, toluene, 10% Pd/C. (ii) Br2 or NIS, CH2Cl2; (iii) Suzuki conditions, arylboronic acids, ethanol abs., (PPh3)4Pd tetrakis(triphenylphosphine)palladium (0), sodium carbonate 2 M; (iv) THF/MeONa.
Scheme 3. Synthesis of 3-(hetero)aroylpyrazolo[1,5-a]quinazoline derivatives. Reagents and conditions: (i) For compound 6d Eaton’s reagent and anisole; for 6e–g: SOCl2 or Cl3CCN/PPh3, then SnCl4 and suitable ArH/HetH; (ii) SOCl2, 2-MeO-PhB(OH)2, toluene, Na2CO3 sol. 2 M; (iii) DMF, K2CO3, MeI.
Scheme 4. Synthesis of 3-(hetero)aroyl-4,5-dihydropyrazolo[1,5-a]quinazolines. Reagents and conditions: (i) AcOH/NaBH3CN.
Figure 2. Concentration-response curves of compounds (A) 5d–f, (B) 6a–d, 6f,g, and (C) 11a,b,d on GABA-induced Cl− currents in Xenopus oocytes expressing recombinant α1β2γ2L GABAA receptors. Data are expressed as the percentage modulation of the response induced by GABA at EC5–10 values, and are the mean ± S.E.M of values obtained from two to nine oocytes. ** p < 0.01; * p < 0.05 Kruskal–Wallis test followed by the Dunn post-hoc test.
Figure 3. Compound 6g antagonized the potentiation of GABA-induced Cl− currents by diazepam in Xenopus oocytes expressing recombinant α1β2γ2L GABAA receptors. Data are expressed as the percentage potentiation of the response induced by GABA at EC5–10 values, and are the mean ± SEM of values obtained from four oocytes. p < 0.05 Mann–Whitney test.
Figure 4. Compound 6g reduced the potentiation of GABA-induced Cl− currents by CGS 9895 (2-p-methoxyphenylpyrazolo[4,3-c]quinolin-3-(5H)-one) in Xenopus oocytes expressing recombinant α1β2 GABAA receptors. Data are expressed as the percentage potentiation of the response induced by GABA at EC5–10 values, and are the mean ± SEM of values obtained from three to six oocytes.
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