title: Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres.
abstract: The ionotropic GABAA receptors (GABAARs) are widely distributed in the central nervous system where they play essential roles in numerous physiological and pathological processes. A high degree of structural heterogeneity of the GABAAR has been revealed and extensive effort has been made to develop selective and potent GABAAR agonists. This review investigates the use of heterocyclic carboxylic acid bioisosteres within the GABAAR area. Several heterocycles including 3-hydroxyisoxazole, 3-hydroxyisoxazoline, 3-hydroxyisothiazole, and the 1- and 3-hydroxypyrazole rings have been employed in order to map the orthosteric binding site. The physicochemical properties of the heterocyclic moieties making them suitable for bioisosteric replacement of the carboxylic acid in the molecule of GABA are discussed. A variety of synthetic strategies for synthesis of the heterocyclic scaffolds are available. Likewise, methods for introduction of substituents into specific positions of the heterocyclic scaffolds facilitate the investigation of different regions in the orthosteric binding pocket in close vicinity of the core scaffolds of muscimol/GABA. The development of structural models, from pharmacophore models to receptor homology models, has provided more insight into the molecular basis for binding. Similar binding modes are proposed for the heterocyclic GABA analogues covered in this review by use of ligand-receptor docking into the receptor homology model and the presented structure-activity relationships. A network of interactions between the analogues and the binding pocket is leaving no room for substituents and underline the limited space in the GABAAR orthosteric binding site when in the agonist conformation.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Jette G
authors.initials: JG
authors.lastname: Petersen
authors.forename: Rikke
authors.initials: R
authors.lastname: Bergmann
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D006571:Heterocyclic Compounds; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid