Galantamine is not a positive allosteric modulator of human alpha 4 beta 2 or alpha 7 nicotinic acetylcholine receptors

Background and Purpose The alkaloid galantamine was originally isolated from the green snowdrop Galanthus woronowii and is currently marketed as a drug for treatment of mild to moderate dementia in patients with Alzheimer's disease. In addition to a well-documented proficiency to inhibit acetylcholinesterase, galantamine has been reported to increase neuronal nicotinic ACh (nACh) receptor function by acting as a positive allosteric modulator. Yet there remains controversy regarding these findings in the literature. To resolve this conundrum, we evaluated galantamine actions at alpha 4 beta 2 and alpha 7, which represent the nACh receptors most commonly associated with mammalian cognitive domains. Experimental Approach alpha 4 beta 2 [in (4)(3)(2)(2) and (4)(2)(2)(3) stoichiometries] and alpha 7 nACh receptors were expressed in Xenopus laevis oocytes and subjected to two-electrode voltage-clamp electrophysiological experiments. Galantamine (10nM to 100 mu M) was evaluated for direct agonist effects and for positive modulation by co-application with sub-maximally efficacious concentrations of ACh. In addition, similar experiments were performed with alpha 7 nACh receptors stably expressed in HEK293 cells using patch-clamp electrophysiology. Key Results In concentrations ranging from 10nM to 1 mu M, galantamine did not display direct agonism nor positive modulatory effects at any receptor combination tested. At concentrations from 10 mu M and above, galantamine inhibited the activity with a mechanism of action consistent with open-channel pore blockade at all receptor types. Conclusion and Implications Based on our data, we conclude that galantamine is not a positive allosteric modulator of alpha 7 or alpha 4 beta 2 receptors, which represent the majority of nACh receptors in mammalian brain.