Development and assessment of a 3D pharmacophore for ligand recognition of BDZR/GABAA receptors initiating the anxiolytic response.
Benzodiazepine receptor (BDZR) ligands are structurally diverse compounds that bind to specific binding sites on GABAA receptors and allosterically modulate 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 hyperthermic effects. In the work presented here, 17 structurally diverse BDZR ligands of the receptors initiating the anxiolytic response have been studied using a systematic computational procedure developed in our laboratory. Using this procedure, a five component 3D recognition pharmacophore was obtained consisting of two proton acceptors, a hydrophobic group, an aromatic electron accepting ring and a ring containing polar moieties, all found in a common geometric arrangement in the 15 compounds with an effect at the anxiolytic end point and absent in two control compounds. The 3D pharmacophore developed was validated by searching 3D databases and finding known BDZR ligands active at the anxiolytic end point, including 1,4-BDZ derivatives, imidazo BDZ and beta-carboline ligands.
Harris
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Molecular Research Institute, Mountain View, CA 94043, USA. dannil@purisima.molres.org
Loew
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D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry*; D019992:Databases as Topic; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011789:Quantum Theory; D011963:Receptors, GABA-A / Q000378:metabolism*; D012984:Software
D014151:Anti-Anxiety Agents; D006571:Heterocyclic Compounds; D008024:Ligands; D011083:Polycyclic Compounds; D011963:Receptors, GABA-A; D001569:Benzodiazepines