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

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 [H-3]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist, to human homo-oligomeric beta 3 and hetero-oligomeric alpha 1 beta 2 gamma 2 gamma-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 beta 3 and alpha 1 beta 2 gamma 2 receptors, with K-i values of 659 pM and 266 nM, respectively. Most of the tested compounds showed selectivity for beta 3 over alpha 1 beta 2 gamma 2 receptors. Among all 1-phenyl-1H-1,2,3-triazoles, the 4-n-propyl-5-ethyl analogue exhibited the highest (> I 133-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 beta 3 and alpha 1 beta 2 gamma 2 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 3 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 beta 3 and alpha 1 beta 2 gamma 2 receptors. A difference in the hydrophobic environment at the 2' position might underlie the selectivity of 1-phenyl-1H-1,2,3-triazoles for beta 3 over alpha 1 beta 2 gamma 2 receptors. The compounds that had high affinity for beta 3 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. (c) 2007 Elsevier Ltd. All rights reseved.