Development and assessment of a 3D pharmacophore for ligand recognition ofBDZR/GABA(A) receptors initiating the anxiolytic response

Benzodiazepine receptor (BDZR) ligands are structurally diverse compounds t hat bind to specific binding sites on GABAA receptors and allosterically mo dulate the effect of GABA on chloride flux. The binding of BDZR ligands to this receptor system results in activity at multiple behavioral end points including anxiolytic; sedative, hyperphagic, anticonvulsant and hyperthermi c effects. In the work presented here, 17 structurally diverse BDZR ligands of the receptors initiating the anxiolytic response have been studied usin g a systematic computational procedure developed in our laboratory. Using t his procedure, a five component 3D recognition pharmacophore was obtained c onsisting of two proton acceptors, a hydrophobic group, an aromatic electro n accepting ring and a ring containing polar moieties, all found in a commo n geometric arrangement in the 15 compounds with an effect at the anxiolyti c end point and absent in two control compounds. The 3D pharmacophore devel oped was validated by searching 3D databases and finding known BDZR ligands active at the anxiolytic end point, including 1, 4-BDZ derivatives, imidaz o BDZ and beta -carboline ligands. (C) 2000 Elsevier Science Ltd. All right s reserved.