title: A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model.
abstract: An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) 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/GABA(A) 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/GABA(A) 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 GABA(A) receptors.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Clayton
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Poe
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Sundari
authors.initials: S
authors.lastname: Rallapalli
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Poonam
authors.initials: P
authors.lastname: Biawat
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Rowlett
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY 10032, USA.
authors.forename: George
authors.initials: G
authors.lastname: Gallos
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY 10032, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Kaczorowski
authors.affiliation: Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Stafford
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA ; Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA ; Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook