title: Bicyclic [b]-heteroannulated pyridazine derivatives--II. Structure-activity relationships in the 6-aryltriazolo-[4,3-b]pyridazine ligands of the benzodiazepine receptor.
abstract: Electronic parameters (molecular electrostatic potential MEP, charge distribution on the nitrogen atoms, dipole moment mu and ionization potential IP) were calculated by semiempirical quantum chemistry methods for 2 sets (X = H and m-CF3, the syn- and anti-rotamers of the latter being considered separately) of the 6-aryl-3-substituted-triazolo[4,3-b]pyridazine ligands of the benzodiazepine receptors (Figure 1; for X and Y c.f. Table 1). The calculations located the deepest MEP minimum near the = N-N = fragment of the triazole ring (Figure 2). Activity of the investigated compounds (1 microM), expressed as % inhibition of in vitro 3H-diazepam (1.5 nM) binding, revealed a significant dependence on IP, which combined in correlation studies with the hydrophobic constants pi X and pi Y and the Swain-Lupton field constant FY gave a 100% explanation of variance (Equations 1-3). However, extrapolation pointed to a compound with excessive hydrophobicity. The dipole moment orientation, roughly consistent with the C(6)-aryl main molecular axis, was considered as another factor controlling the docking of the investigated triazolopyridazine ligands to the benzodiazepine receptor (Figure 3). A model of the triazolopyridazine-benzodiazepine receptor interaction was proposed (Figure 4).
authors.affiliation: Institute of General and Ecological Chemistry, Technical University, Lódź, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.forename: J
authors.initials: J
authors.lastname: Lange
authors.forename: W
authors.initials: W
authors.lastname: Kwiatkowski
authors.forename: M
authors.initials: M
authors.lastname: Gniewosz
authors.forename: J
authors.initials: J
authors.lastname: Plenkiewicz
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004563:Electrochemistry; D066298:In Vitro Techniques; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D008024:Ligands; D011720:Pyrazoles; D011724:Pyridazines; D011963:Receptors, GABA-A; C021604:CL 218872; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one