4-OXYSTILBENE COMPOUNDS ARE SELECTIVE LIGANDS FOR NEURONAL NICOTINIC ALPHA-BUNGAROTOXIN RECEPTORS

1 Starting from the structure of an old 4-oxystilbene derivate with ga nglioplegic activity (MG624), we synthesized two further derivates (F2 and F3) and two stereoisomers of F3 (F3A and F3B), and studied their selective effect on neuronal nicotinic acetylcholine receptor (AChR) s ubtypes. 2 MG 624, F3, F3A and F3B inhibited of I-125-alpha Bungarotox in (alpha Bgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited I-125-alpha Bgtx binding to TE671 cell -expressed muscle-type AChR only at much higher concentrations. 3 We i mmobilized the alpha 7, beta 2 and beta 4 containing chick neuronal ni cotinic AChR subtypes using anti-subunit specific antibodies. MG 624, F3, F3A and F3B inhibited I-125-alpha Bgtx binding to the alpha 7-cont aining receptors with nM affinity, but inhibited H-3-Epi binding to be ta 2-containing receptors only at very high concentrations (more than 35 mu M); their affinity for the beta 4-containing receptors was ten t imes more than for the beta 2-containing subtype. 4 Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte-expres sed chick alpha 7 receptors with an IC50 of respectively 94 and 119 nM . 5 High doses of both MG 624 and F3 depressed the contractile respons e to vagus nerve stimulation in guinea pig nerve-stomach preparations although at different IC(50)s (49.4 vs 166.2 mu M) The effect of MG624 on rat nerve-hemidiaphragm preparations was 33 times less potent than that of F3 (IC50 486 vs 14.5 mu M). 6 In conclusion, MG624 and F3 hav e a high degree of antagonist selectivity for neuronal nicotinic alpha Bgtx receptors containing the alpha 7 subunit.