PubMed1994
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).