title: GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology.
abstract: A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown for only a few orthosteric ligands. Still, these examples show that it is indeed possible to obtain orthosteric subtype selectivity and they serve as models for further development in the orthosteric GABAAR ligand area. This review presents the very few existing structural classes of orthosteric GABAAR antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Krall
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.affiliation: Institute for Photonics and Advanced Sensing (IPAS) and School of Chemistry and Physics, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Niels
authors.initials: N
authors.lastname: Krogsgaard-Larsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Troels E
authors.initials: TE
authors.lastname: Sørensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Uffe
authors.initials: U
authors.lastname: Kristiansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: bfr@sund.ku.dk.
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000818:Animals; D001665:Binding Sites; D054333:Drug Partial Agonism; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
chemical_list: D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A
keywords: 4-PIOL; GABA(A) receptor antagonists; GABA(A) receptor partial agonists; GABA(A) receptors; Receptor homology models; Structure–activity relationship studies; Tonic inhibition