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

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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 π-electron rich aromatic (PAR) zone; (b) two electron-rich zones δ1 and δ2 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 δ1 zone, accounts forR andS differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.

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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

β-Carbolines:

BCC (3-carboethoxy-β-carboline)

Benzodiazepines: Diazepam:

DZ (7-chloro-1,3-dihydro-1-methyl-5 phenyl-2H-1,4-benzodiazepin-2-one)

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Authors and Affiliations

  1. Department of Molecular Pharmacochemistry, Centre de Neurochimie du CNRS et Unité 44 de l'INSERM, 5 rue Blaise Pascal, 67084, Strasbourg Cedex, France

    Souhail Tebib, Jean-Jacques Bourguignon & Camille-Georges Wermuth

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  1. Souhail Tebib
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  2. Jean-Jacques Bourguignon
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  3. Camille-Georges Wermuth
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Tebib, S., Bourguignon, JJ. & Wermuth, CG. The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands. J Computer-Aided Mol Des 1, 153–170 (1987). https://doi.org/10.1007/BF01676959

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