Selective effects of a 4‐oxystilbene derivative on wild and mutant neuronal chick α7 nicotinic receptor

Abstract

We assessed the pharmacological activity of triethyl‐(β‐4‐stilbenoxy‐ethyl) ammonium (MG624), a drug that is active on neuronal nicotinic receptors (nicotinic AChR). Experiments on the major nicotinic AChR subtypes present in chick brain, showed that it inhibits the binding of [¹²⁵I]‐αBungarotoxin (αBgtx) to the α7 subtype, and that of [³H]‐epibatidine (Epi) to the α4β2 subtype, with K_i values of respectively 106 nM and 84 μM. MG624 also inhibited ACh elicited currents (I_ACh) in the oocyte‐expressed α7 and α4β2 chick subtypes with half‐inhibitory concentrations (IC₅₀) of respectively 109 nM and 3.2 μM. When tested on muscle‐type AChR, it inhibited [¹²⁵I]‐αBgtx binding with a K_i of 32 μM and ACh elicited currents (I_ACh) in the oocyte‐expressed α1β1γδ chick subtype with an IC₅₀ of 2.9 μM. The interaction of MG624 with the α7 subtype was investigated using an α7 homomeric mutant receptor with a threonine‐for‐leucine 247 substitution (L247T α7). MG624 did not induce any current in oocytes expressing the wild type α7 receptor, but did induce large currents in the oocyte‐expressed L247T α7 receptor. The MG624 elicited current (I_MG624) has an EC₅₀ of 0.2 nM and a Hill coefficient nH of 1.9, and is blocked by the nicotinic receptor antagonist methyllycaconitine (MLA). These binding and electrophysiological studies show that MG624 is a potent antagonist of neuronal chick α7 nicotinic AChR, and becomes a competitive agonist following the mutation of the highly conserved leucine residue 247 located in the M2 channel domain. British Journal of Pharmacology (1999) 126, 285–295; doi:10.1038/sj.bjp.0702299