KYNURENIC ACID-DERIVATIVES INHIBIT THE BINDING OF NERVE GROWTH-FACTOR(NGF) TO THE LOW-AFFINITY P75 NGF RECEPTOR

The ability of a series of substituted kynurenic acids, thienopyridino necarboxylic acids, and related compounds to inhibit the binding of ne rve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated i n a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR (p75(ext)) fixed to streptavid in-coated plastic wells. Two compounds, 6-aminokynurenic acid (5h) and the 3-methyl ester of ethyl-7-oxo-thieno[3,2-b]pyridine-3,5-dicarboxy lic acid (16), were found to inhibit the binding of [I-125]NGF to p75( ext) with IC50 values in the low micromolar range. Other amino-substit uted kynurenic acids also possessed activity at slightly higher concen trations. Several structural features seem to be essential, including the carboxylic acid, a polar group on the benzene ring (or thiophene r ing, in the case of analogues of 16), and the C-4 carbonyl group in th e pyridinone ring. These compounds were also found to inhibit the bind ing of [I-125]NGF to its receptors in membranes from PC12 cells (which express p75 as well as trk(a) receptors for NGF) and DG44-CHO cells ( transfected with full length p75 NGFR). The available data for 5h and 16 do not allow the determination of whether the effects of these comp ounds are mediated by their interaction with NGF or the NGF receptors.