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Phenylacetic acids and the structurally related non‐steroidal anti‐inflammatory drug diclofenac bind to specific γ‐hydroxybutyric acid sites in rat brain
Author(s) -
Wellendorph Petrine,
Høg Signe,
Skonberg Christian,
BräunerOsborne Hans
Publication year - 2009
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2008.00664.x
Subject(s) - phenylacetic acid , chemistry , pharmacology , ligand (biochemistry) , diclofenac , metabolite , stereochemistry , binding site , mechanism of action , affinities , receptor , biochemistry , in vitro , biology
γ‐Hydroxybutyric acid (GHB) is a proposed neurotransmitter or neuromodulator with a yet unresolved mechanism of action. GHB binds to both specific high‐affinity GHB binding sites and to γ‐aminobutyric acid subtype B (GABA B ) receptors in the brain. To separate specific GHB effects from GABA B receptor effects, it is imperative to develop GHB selective and potent compounds. We generated the compound, 4‐(biphen‐4‐yl)‐4‐hydroxybutyric acid, which is the 4‐hydroxyl analogue of the non‐steroidal anti‐inflammatory drug (NSAID) fenbufen (referred to as γ‐hydroxyfenbufen). When measured in a rat brain homogenate [ 3 H]NCS‐382 binding assay, γ‐hydroxyfenbufen inhibited [ 3 H]NCS‐382 binding with a 10‐fold higher affinity than GHB ( K i 0.44 μ m ), thus establishing it as a novel lead structure. The active metabolite of fenbufen, 4‐biphenylacetic acid inhibited [ 3 H]NCS‐382 binding with a twofold higher affinity than GHB. Measuring the affinities of structurally related NSAIDs for the [ 3 H]NCS‐382 site identified diclofenac, a clinically relevant NSAID (Voltaren ® , Diclon ® ) of the phenylacetic acid (PAA) type, as a GHB ligand ( K i value of 5.1 μ m ). Other non‐NSAID PAAs also exhibited affinities similar to GHB. Our data raise the interesting possibility that the widely used over‐the‐counter drug compound, diclofenac, might affect GHB binding at relevant clinical dosages. Furthermore, the identification of PAAs as GHB ligands supplies new information about the structural preferences of the GHB ligand‐binding site.