title: Quantitative structure-activity relationship study of some benzodiazepine-receptor ligands having inverse agonist/antagonist and agonist actions.
abstract: Quantitative structure-activity relationship (QSAR) analyses of three different series of benzodiazepine ligands, pyridodiindoles, and beta-carbolines, having inverse agonist/antagonist and agonist actions have been performed with a view to understanding their likely mode of action at the benzodiazepine-receptor (BzR). From this study, the in vitro radioligand displacement activities of substituted 7,12-dihydropyrido[3,2-b: 5,4-b']diindoles (Figure 1) were found to be significantly correlated with resonance effect of R-substituents, van der Waals volumes at positions-1 and -3, hydrophobic constant at position-2 and field effect at position-4 of X-substituents. For 3-substituted beta-carbolines, a similar analysis has established that R-substituents at position-3 of beta-carbolines (Figure 2) are involved in strong hydrophobic interaction with some hydrophobic pocket on the receptor. For the analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carbolines-3-carboxylic acid ethyl ester (Figure 3), however, the combined hydrophobicities of 6- and 4-substituents were shown to be important in determining ligand binding behaviour. The significant correlations so obtained are in agreement with the proposed models (Figures 4 and 5) of pharmacophores of inverse agonist/antagonist and of agonist sites at the BzR.
authors.affiliation: Department of Chemistry, S.K. Government College, Sikar, India.
authors.forename: R C
authors.initials: RC
authors.lastname: Sharma
authors.forename: T N
authors.initials: TN
authors.lastname: Ojha
authors.forename: S
authors.initials: S
authors.lastname: Tiwari
authors.forename: P
authors.initials: P
authors.lastname: Singh
mesh_terms: D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D015394:Molecular Structure; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D007211:Indoles; D011963:Receptors, GABA-A; C042569:ZK 93423