Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues

Allosteric modulatory effects of 12 biphenyl derivatives of diflunisal and two fenamates were studied on A-type receptors of GABA (GABA(A)R) via [H-3]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. (c) 2006 Elsevier Ltd. All rights reserved.