4-Oxystilbene compounds are selective ligands for neuronal nicotinic αBungarotoxin receptors

Abstract

1. Starting from the structure of an old 4-oxystilbene derivate with ganglioplegic 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) subtypes.

2. MG 624, F3, F3A and F3B inhibited of ¹²⁵I-αBungarotoxin (αBgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited ¹²⁵I-αBgtx binding to TE671 cell-expressed muscle-type AChR only at much higher concentrations.

3. We immobilized the α7, β2 and β4 containing chick neuronal nicotinic AChR subtypes using anti-subunit specific antibodies. MG 624, F3, F3A and F3B inhibited ¹²⁵I-αBgtx binding to the α7-containing receptors with nM affinity, but inhibited ³H-Epi binding to β2-containing receptors only at very high concentrations (more than 35 μM); their affinity for the β4-containing receptors was ten times more than for the β2-containing subtype.

4. Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte-expressed chick α7 receptors with an IC₅₀ of respectively 94 and 119 nM.

5. High doses of both MG 624 and F3 depressed the contractile response to vagus nerve stimulation in guinea pig nerve-stomach preparations although at different IC₅₀s (49.4 vs 166.2 μM) The effect of MG624 on rat nerve-hemidiaphragm preparations was 33 times less potent than that of F3 (IC₅₀ 486 vs 14.5 μM).

6. In conclusion, MG624 and F3 have a high degree of antagonist selectivity for neuronal nicotinic αBgtx receptors containing the α7 subunit.

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