Based on a pharmacophore model of the benzodiazepine-binding site of GABA(A) receptors, a series of 2-aryl-2,6-dihydro1,2,4triazolo4,3-cquinazoline-3,5-diones (structure type I) were designed, synthesized, and identified as high-affinity ligands of the binding site. For several compounds, K(i) values of around 0.20nM were determined. They show a structural resemblance with the previously described 2-phenyl-2H-pyrazolo4,3-cquinolin-3(5H)-ones (II) and 2-phenyl-1,2,4triazolo1,5-aquinoxalin-4(5H)-one (III). The 9-bromo substituted compounds 8a-d were prepared in an 8-step synthesis in an overall yield of approximately 40, and a library of 9-substituted analogues was prepared by cross-coupling reactions. Compound 8e, 21, 22, and 24 were tested on recombinant rat alpha(1)beta(3)gamma(2), alpha(2)beta(3)gamma(2), alpha(3)beta(3)gamma(2), and alpha(5)beta(3)gamma(2) subtypes, and displayed selectivity for the alpha(1)beta(3)gamma(2) isoform.
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