The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands

Abstract

Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor. A unique pharmacophore model was derived which involves six critical zones: (a) a pi-electron rich aromatic (PAR) zone; (b) two electron-rich zones delta 1 and delta 2 placed at 5.0 and 4.5 A respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR). The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the delta 1 zone, accounts for R and S differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.

Differential potentiation of GABAA receptor function by two stereoisomers of diimidazoquinazoline analogues

“…Studies with molecular mechanics showed that the diimidazoquinazoline ring is largely plantar and the methyl substituent at R2 and R3 projected below and above the planar ring, respectively (Figure 7) (Cooper, 1986;Villar et al, 1989 (Villar et al, 1991). In this study, on the other hand, the differential agonistic activity of the two diimidazoquinazoline stereoisomers clearly points out the key functional pharmacophore for benzodiazepine receptor ligands and appears to favour one particular proposal that the agonistic activity can be attributed to the presence of a bulky group in an out-of-plane region where the 5-phenyl group of benzodiazepines has also been assigned (Tebib et al, 1987). This proposal was formulated from computational modelling of diverse chemical structures including benzodiazepines, pyrazoquinolones, cyclopyrrolones, P-carbolines and imidazopyridines.…”

“…been proposed to explain the in vivo efficacy of various ligands on the basis of computational modelling studies (Tebib et al, 1987;Villar et al, 1989;. Knowledge of the key functional determinants for benzodiazepine receptor ligands in cloned GABAA receptors would be useful for understanding the ligand-receptor interactions at the molecular level and for developing new ligands with unique pharmacological and therapeutic profiles.…”

Structure of suriclone, a benzodiazepine receptor agonist

“…Features of these models are similar to our earlier benzodiazepine receptor model (Codding & Muir, 1985) which was based on the structures of inverse agonist ligands. In particular, Tebib et al (1987) find a hydi'ophobic binding site that discriminates between agonist/antagonist/inverse-agonist activity depending upon the substitution pattern of the group that binds in that pocket; this was identified as site three in our earlier model. The model proposed by Tebib and co-workers would place the (A) and (B) rings of suriclone in this pocket; such placement suggests that the greater activity of suriclone over zopiclone may be due to the greater ability of suricione to fill this hydrophobic pocket.…”

“…These pharmacological properties have been the basis for assuming that suriclone binds to the benzodiazepine receptor. Two recently published models (Borea eta/., 1987;Tebib, Bourguignon & Wermuth, 1987)include either suriclone or the related molecule, zopiclone, in their proposal for the agonist recognition site. Both of these models propose that an aromatic binding site recognizes the pyrrolidone and dithiacyclohexene rings (C and D) and that two agonist-determining regions bind the chloro-diazanaphthalene ring (A and B) and the saturated piperazine ring (E).…”

“…3 shows the two superpositions of suriclone and the active conformation of the potent benzodiazepine agonist, clonazepam (Chananont, Hamor & Martin, 1979); the left panel compares R suriclone to clonazepam and the right panel compares S suriclone. This figure was prepared by using two models for the receptor site (Codding & Muir, 1985;Tebib et al, 1987) to identify the ligand features that should superimpose. The superposition was calculated by a least-squares fit of the positions of five atoms from each structure to produce an overlay of rings (C) and (D) of suriclone with the benzodiazepine portion of clonazepam; the average distance between pairs of matched atoms was 0.22 ,~ for the S enantiomer and 0.24,/~ for the R enantiomer.…”