A Review of the Updated Pharmacophore for the Alpha 5 GABAA Benzodiazepine Receptor ModelReportar como inadecuado

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International Journal of Medicinal Chemistry - Volume 2015 2015, Article ID 430248, 54 pages -

Review Article

Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA

Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA

Department of Anesthesiology, Columbia University, New York, NY 10032, USA

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA

Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA

Received 11 February 2015; Revised 16 June 2015; Accepted 2 July 2015

Academic Editor: Hussein El-Subbagh

Copyright © 2015 Terry Clayton et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


An updated model of the GABAA benzodiazepine receptor pharmacophore of the α5-BzR-GABAA subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR-GABAA α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 1 which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator PAM, SH-053-2′F-R-CH3 2, has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz-GABAA receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABAA receptors.

Autor: Terry Clayton, Michael M. Poe, Sundari Rallapalli, Poonam Biawat, Miroslav M. Savić, James K. Rowlett, George Gallos, Char

Fuente: https://www.hindawi.com/


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