title: Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues.
abstract: Allosteric modulatory effects of 12 biphenyl derivatives of diflunisal and two fenamates were studied on A-type receptors of GABA (GABAAR) via [3H]4'-ethynylbicycloorthobenzoate (EBOB) binding to synaptic membrane preparations of rat forebrain. A simplified ternary allosteric model was used to determine binding affinities of the compounds and the extents of cooperativity with GABA. Structure activity analysis revealed that 4-hydroxy substituents of the biphenyls contribute to their micromolar binding affinities more than 3-carboxyl groups. Electron-withdrawing fluorinated substituents, especially in ortho position, were also advantageous. These factors also strongly enhanced the cooperativity with GABA binding. The correlation between displacing potency of the allosteric agents and cooperativity with GABA suggests that these processes are associated with common mechanisms. The pharmacological relevance of these interactions is discussed. These data help to differentiate the structural requirements of these agents to act on GABAergic neurotransmission versus nonsteroidal anti-inflammatory effects.
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, POB 17, Hungary. mikko.uusi-oukari@utu.fi
authors.forename: Mikko
authors.initials: M
authors.lastname: Uusi-Oukari
authors.forename: Gábor
authors.initials: G
authors.lastname: Maksay
mesh_terms: D000345:Affinity Labels / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D004061:Diflunisal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000737:chemistry; D008297:Male; D008469:Meclofenamic Acid / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000345:Affinity Labels; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011963:Receptors, GABA-A; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; D017665:Hydroxyl Radical; D008469:Meclofenamic Acid; D005680:gamma-Aminobutyric Acid; D004061:Diflunisal