4-Oxystilbene compounds are selective ligands for neuronal nicotinic alphaBungarotoxin receptors.
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-alphaBungarotoxin (alphaBgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited 125I-alphaBgtx binding to TE671 cell-expressed muscle-type AChR only at much higher concentrations. 3. We immobilized the alpha7, beta2 and beta4 containing chick neuronal nicotinic AChR subtypes using anti-subunit specific antibodies. MG 624, F3, F3A and F3B inhibited 125I-alphaBgtx binding to the alpha7-containing receptors with nM affinity, but inhibited 3H-Epi binding to beta2-containing receptors only at very high concentrations (more than 35 microM); their affinity for the beta4-containing receptors was ten times more than for the beta2-containing subtype. 4. Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte-expressed chick alpha7 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 microM) The effect of MG624 on rat nerve-hemidiaphragm preparations was 33 times less potent than that of F3 (IC50 486 vs 14.5 microM). 6. In conclusion, MG624 and F3 have a high degree of antagonist selectivity for neuronal nicotinic alphaBgtx receptors containing the alpha7 subunit.
Gotti
C
C
CNR Cellular and Molecular Pharmacology Center, Department of Medical Pharmacology, University of Milan, Italy.
Balestra
B
B
Moretti
M
M
Rovati
G E
GE
Maggi
L
L
Rossoni
G
G
Berti
F
F
Villa
L
L
Pallavicini
M
M
Clementi
F
F
D000818:Animals; D000918:Antibody Specificity; D002038:Bungarotoxins / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D006168:Guinea Pigs; D007457:Iodine Radioisotopes; D009474:Neurons / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D013267:Stilbenes / Q000378:metabolism* / Q000494:pharmacology; D009435:Synaptic Transmission; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D002038:Bungarotoxins; D007457:Iodine Radioisotopes; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D013267:Stilbenes