title: 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.
abstract: 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.
authors.affiliation: Drug Theoretics & Cheminformatics Lab, Division of Medicinal & Pharmaceutical Chemistry Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Dalai
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Leonard
authors.forename: Kunal
authors.initials: K
authors.lastname: Roy
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000081:Acetamides; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; C059194:2-phenylimidazole; C023666:pyridine