Synthesis, 3D-QSAR, and docking studies of 1-phenyl-1H-1,2,3-triazoles as selective antagonists for β3 over α1β2γ2 GABA receptors Original Research Article

A series of 16 1-phenyl-1H-1,2,3-triazoles with substituents at both the 4- and 5-positions of the triazole ring were synthesized, and a total of 49 compounds, including previously reported 4- or 5-monosubstituted analogues, were examined for their ability to inhibit the specific binding of [3H]4′-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist, to human homo-oligomeric β3 and hetero-oligomeric α1β2γ2 γ-aminobutyric acid (GABA) receptors. Among all tested compounds, the 4-n-propyl-5-chloromethyl analogue of 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole showed the highest level of affinity for both β3 and α1β2γ2 receptors, with Ki values of 659 pM and 266 nM, respectively. Most of the tested compounds showed selectivity for β3 over α1β2γ2 receptors. Among all 1-phenyl-1H-1,2,3-triazoles, the 4-n-propyl-5-ethyl analogue exhibited the highest (>1133-fold) selectivity, followed by the 4-n-propyl-5-methyl analogue of 1-(2,6-dibromo-4-trifluoromethylphenyl)-1H-1,2,3-triazole with a >671-fold selectivity. The 2,6-dichloro plus 4-trifluoromethyl substitution pattern on the benzene ring was found to be important for the high affinity for both β3 and α1β2γ2 receptors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) provided similar contour maps, revealing that an electronegative substituent at the 4-position of the benzene ring, a compact, hydrophobic substituent at the 4-position of the triazole ring, and a small, electronegative substituent at the 5-position of the triazole ring play significant roles for the high potency in β3 receptors. Molecular docking studies suggested that the putative binding sites for 1-phenyl-1H-1,2,3-triazole antagonists are located in the channel-lining 2′-6′ region of the second transmembrane segment of β3 and α1β2γ2 receptors. A difference in the hydrophobic environment at the 2′ position might underlie the selectivity of 1-phenyl-1H-1,2,3-triazoles for β3 over α1β2γ2 receptors. The compounds that had high affinity for β3 receptors with homology to insect GABA receptors showed insecticidal activity against houseflies with LD50 values in the pmol/fly range. The information obtained in the present study should prove helpful for the discovery of selective insect control chemicals.