title: Synthesis, 3D-QSAR, and docking studies of 1-phenyl-1H-1,2,3-triazoles as selective antagonists for beta3 over alpha1beta2gamma2 GABA receptors.
abstract: 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 [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist, to human homo-oligomeric beta3 and hetero-oligomeric alpha1beta2gamma2 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 beta3 and alpha1beta2gamma2 receptors, with K(i) values of 659pM and 266nM, respectively. Most of the tested compounds showed selectivity for beta3 over alpha1beta2gamma2 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 beta3 and alpha1beta2gamma2 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 beta3 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 beta3 and alpha1beta2gamma2 receptors. A difference in the hydrophobic environment at the 2' position might underlie the selectivity of 1-phenyl-1H-1,2,3-triazoles for beta3 over alpha1beta2gamma2 receptors. The compounds that had high affinity for beta3 receptors with homology to insect GABA receptors showed insecticidal activity against houseflies with LD(50) values in the pmol/fly range. The information obtained in the present study should prove helpful for the discovery of selective insect control chemicals.
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane, Japan.
authors.forename: Mohammad Sayed
authors.initials: MS
authors.lastname: Alam
authors.forename: Jia
authors.initials: J
authors.lastname: Huang
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ozoe
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsumura
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ozoe
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018756:GABA Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006793:Houseflies / Q000187:drug effects; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018756:GABA Antagonists; D007306:Insecticides; D014230:Triazoles