Bicyclic [b]-heteroannulated pyridazine derivatives--II. Structure-activity relationships in the 6-aryltriazolo-[4,3-b]pyridazine ligands of the benzodiazepine receptor.

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).