The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands |
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Authors: | Souhail Tebib Jean-Jacques Bourguignon Camille-Georges Wermuth |
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Affiliation: | (1) Department of Molecular Pharmacochemistry, Centre de Neurochimie du CNRS et Unité 44 de l'INSERM, 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France |
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Abstract: | Summary 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 -electron rich aromatic (PAR) zone; (b) two electron-rich zones 1 and 2 placed at 5.0 and 4.5 Å 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 1 zone, accounts forR andS differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.Abbreviations Pyrazoloquinolines CGS (2-phenyl-2,5-dihydro pyrazolo [4,3-c] quinoline-3 (3H)-one) - Cinnolinones CIN (2-(4-methoxyphenyl)-benzo [h] 3-cinnolinone - Triazolophthalazines TZPH (3-(4-methoxyphenyl)-6 pyrrolidinotriazolo [4,3-a] phthalazine - Cyclopyrrolones RP 27267, CLO ([6-(5-chloro-2-pyridyl)-6,7-dihydro-7 oxo-5H-pyrrolo [3,4-b]pyrazin-5-yl] 4-methyl-l-piperazine carboxylate) - Phenylquinolines PK (phenyl-2 (morpholinocarbonyl methyl oxy)-4 quinoline - -Carbolines BCC (3-carboethoxy--carboline) - Benzodiazepines: Diazepam DZ (7-chloro-1,3-dihydro-1-methyl-5 phenyl-2H-1,4-benzodiazepin-2-one) |
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Keywords: | Benzodiazepine pharmacophore Cyclopyrrolones Triazolopyridazines /content/r4755m9l3615404v/xxlarge946.gif" alt=" beta" align=" MIDDLE" BORDER=" 0" >-Carbolines Pyrazoloquinolines |
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