Exploring QSAR of peripheral benzodiazepine receptor binding affinity of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides using physico-chemical descriptors.

The present QSAR study has attempted to explore the structural and physicochemical requirements of ligands N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for binding with peripheral benzodiazepine receptor (PBR). The calculated partition coefficient values show parabolic relations with the PBR binding affinity, suggesting that the binding affinity increases with increase in the partition coefficient of the compounds until it reaches the critical value after which the affinity decreases. The critical value of logP is within range of 6.052-6.410. Furthermore, positive Wang-Ford.charge values of carbonyl oxygens of the glyoxamide moiety and negative Wang-Ford charge value of the glyoxamide nitrogen are conducive for the binding affinity. Again, the indole moiety should have favorable charge distribution. Higher values of the parameters dipole moment (Dipole) and moment of inertia (I_z) of the ligands are conducive for the binding affinity. The presence of hydrogen atom at R2 and cyclic moiety at R1 and R2 positions are detrimental to the binding affinity.

Exploring selectivity requirements for peripheral versus central benzodiazepine receptor binding affinity: QSAR modeling of 2-phenylimidazo[1,2-a]pyridine acetamides using topological and physicochemical descriptors.

Considering the potential of peripheral benzodiazepine receptor (PBR) ligands in therapeutic applications and clinical benefit in the management of a large spectrum of different indications, quantitative structure-activity relationship (QSAR) study has been attempted to explore the structural and physicochemical requirements for selectivity of 2-phenylimidazo[1,2-a]pyridineacetamides for binding with peripheral over central benzodiazepine receptors (CBRs). For PBR binding affinity, molar refractivity (MR) shows a parabolic relation with binding affinity suggesting that binding affinity increases with increase in volume of the compounds, until it reaches the critical value, after which the affinity decreases. The negative coefficients of S_aaN and S_ssNH indicate that binding affinity increases with decrease in E-state value of (N/) (aromatic nitrogen) and HN< (secondary amino group) fragments. The coefficient of 3XVC and JX term indicates the importance of shape and branching for binding affinity. For CBR binding affinity, lipophilicity of molecules is detrimental to the binding affinity, while presence of hydrogen at Y position is conducive to the activity. Selectivity pattern of these ligands for peripheral (cortex) over central receptors requires the presence and absence of methyl group at R2 and R3 positions respectively, and shows the importance of MR and shape parameter. Similarly, selectivity of these ligands for peripheral (ovary) over central receptors requires the presence and absence of methyl group at R2 and R3 positions respectively, presence of phenyl group at R1 and R2 positions and selectivity relation shows importance of MR, shape and branching.