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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 .

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.

PubMed ID: 30901916
PMC ID: PMC6470557
Article link: Int J Mol Sci
Grant support: [+]

Species referenced: Xenopus
Genes referenced: gabarap phb1 slc5a5

Article Images: [+] show captions
References [+] :
Alexander, THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand-gated ion channels. 2017, Pubmed