Synthetic and computer-assisted analysis of the structural requirements for selective, high-affinity ligand binding to diazepam-insensitive benzodiazepine receptors

Abstract

Several 1,4-diazepines were recently reported to bind with high affinities to the "diazepam-insensitive" (DI) isoform of the benzodiazepine receptor (BzR) (Korpi, E.R.; Uusi-Oukari, M.; Wegelius, K. Eur. J. Pharm. 1992, 213, 323-329. Wong, G.; Skolnick, P. Eur. J. Pharmacol. Mol. Pharm. Sec. 1992, 225, 63-68). However, only the putative ethanol antagonist 1 (Ro 15-4513) displayed modest selectivity for the DI site compared to other "diazepam-sensitive" (DS) BzR isoforms. In order to probe the requirements for selective, high-affinity binding to the DI site, the affinities of 47 benzodiazepines have been determined at both DI and DS BzR sites. In addition, single X-ray crystallographic analyses for three of these derivatives, 5 (Ro 17-1812), 6 (Ro 16-6028), and 42 (Ro 14-5974), are reported. The radioligand binding studies reveal that modifications to the 3-, 7-, and 8-positions of 6-oxoimidazo[1,5-alpha] [1,4]benzodiazepines have a marked influence on the Ki(DI)/Ki(DS) ratios. In order to more precisely determine the structural requirements for both high affinity and selectivity at DI BzR relative to DS, 3D-QSAR analyses were carried out on ligand affinities at both of these BzR isoforms. This analysis was based, in part, on the new X-ray crystallographic data. Satisfactory cross-validated regression equations were obtained individually for the logarithms of ligand affinities at DI and DS as well as for the differences of the logarithms of their affinities at these two isoforms (cross-validated R2 > 0.70 for all three regression equations). The steric and electrostatic 3D-QSAR DI and DS maps are in qualitative accord with the structure-activity relationship (SAR) data. Furthermore, the DI and DI/DS maps may be useful in the design of ligands with enhanced DI affinity and DI/DS selectivity, respectively.

Structural Requirements for Imidazobenzodiazepine Binding to GABAA Receptors

“…Consistent with this idea, large substitutions at the 3Ј position of i-BZDs are not tolerated. For example, as the size of the ester group increases from CO 2 CH 2 CH 3 (Ro 15-1788) to CO 2 CH 2 C(CH 3 ) 3 , binding affinity is reduced 100-fold (Wong et al, 1993). Mutations at ␥ 2 A79 affect Ro 15-4513 binding to a greater extent than Ro 15-1788 (Table 1).…”

“…Interestingly, i-BZDs with small 3Ј substituents (e.g., CO 2 CH 3 ) also have decreased binding affinities (Wong et al, 1993), suggesting that there may be an optimal size relationship between the 3Ј substituent and the binding site. Mutation of ␥ 2 A79 to a smaller residue (e.g., glycine) as well as to larger residues (e.g., phenylalanine, tyrosine) significantly decreases Ro 15-4513 and Ro 15-1788 binding affinities (Table 1) and suggests that size of the side chain at this position influences i-BZD binding affinity.…”

Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors

“…6) in order to compare with the qualitative SAR and to obtain a general understanding of the QSAR. In the case of the selectivity analysis, the contour plots were illustrative for identifying features important for selectivity, an approach also used in other studies [38,39]. The contour plot of the AT 2 receptor affinity model (Fig.…”

Quantitative Structure–Activity Relationship Studies for the Binding Affinities of Imidazobenzodiazepines for the α6 Benzodiazepine Receptor Isoform Utilizing Optimized Blockwise Variable Combination by Particle Swarm Optimization for Partial Least Squares Modeling

“…Two 3-cyclo-propyl carbonyl imidazobenzodiazepines, RU 33965 and RU 34030, were tested for their ability to modulate GA-BA A synaptic transmission in rat cerebellar slices by Ward et al [6]; Gu et al [7] synthesized a series of imidazo [1,5-a] [1,4]-benzodiazepine esters and evaluated the affinities at both Diazepam-Insensitive (DI) and Diazepam-Sensitive (DS) subtypes of the BzR. Wong et al [8] also studied the ligand affinities at both of these BzR isoforms. Zhang et al [9] synthesized a series of novel imidazobenzodiazepines and described their affinities for DS and DI GABA A receptors.…”