Jerzy Lange

Structure-activity relationship investigations of the modulating effect of core substituents on the affinity of pyrazoloquinolinone congeners for the benzodiazepine receptor.

A series of 6- and 7-substituted-2-arylpyrazolo[4,3-c]quinolin-3-ones was synthesized and tested in vitro for binding with the benzodiazepine receptor in competition with [3H]flunitrazepam. Electronic parameters (molecular electrostatic potential (MEP), charge distribution on the nitrogen atoms, dipole moment mu, and ionization potential (IP)) were calculated for the compounds by semi-empirical quantum chemistry methods. Lipophilicity of the compounds, expressed as logarithm of the octanol-water partition coefficient (log P), was calculated by the program Pallas. A quantitative correlation of the biological data with molecular parameters revealed a significant dependence (r = 0.95) of the activity on hydrophobic constants of the substituents, log P, and magnitude of the MEP minimum associated with the carbonyl oxygen atom.

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).

Direct Pyridazine Ring Synthesis from β-Cyano Esters. A Facile Synthesis of the Derivatives of Tetrahydro-3,6-pyridazinedione 3-Hydrazone

Abstract 4-Substituted tetrahydro-3,6-pyridazinedione 3-hydrazones (2) (or their 3-hydrazino tautomers 3), useful intermediates in the synthesis of bicyclic pyridazine derivatives, were prepared in satisfactory yields in the reaction of the corresponding alkyl 3-substituted 3-cyanopropionates with hydrazine hydrate.