Allosteric Modulator Desformylflustrabromine Relieves the Inhibition of α2β2 and α4β2 Nicotinic Acetylcholine Receptors by β-Amyloid1-42 Peptide

Nicotinic acetylcholine receptors (nAChRs) are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer's disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of beta amyloid (A beta(1-42)) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for alpha 4 beta 2 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the alpha 2 beta 2 nAChR subtype was not known. The action of dFBr was tested on alpha 2 beta 2 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the alpha 2 beta 2 receptor. Next we tested whether dFBr had any effect on the previously known block of both the alpha 4 beta 2 and alpha 2 beta 2 receptors by A beta(1-42). We found that the functional blockade of ACh-induced currents in oocytes expressing alpha 4 beta 2 and alpha 2 beta 2 receptors by A beta(1-42) was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both alpha 4 beta 2 and alpha 2 beta 2 subtypes of nAChRs and that it also relieves the blockade of these receptors by A beta(1-42). This study demonstrates that PAMs for the non-alpha 7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders.