Kowal_2018_Br.J.Pharmacol_175_2911

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 alpha4beta2 and alpha7, which represent the nACh receptors most commonly associated with mammalian cognitive domains. EXPERIMENTAL APPROACH: alpha4beta2 [in (alpha4)3 (beta2)2 and (alpha4)2 (beta2)3 stoichiometries] and alpha7 nACh receptors were expressed in Xenopus laevis oocytes and subjected to two-electrode voltage-clamp electrophysiological experiments. Galantamine (10 nM to 100 muM) 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 alpha7 nACh receptors stably expressed in HEK293 cells using patch-clamp electrophysiology. KEY RESULTS: In concentrations ranging from 10 nM to 1 muM, galantamine did not display direct agonism nor positive modulatory effects at any receptor combination tested. At concentrations from 10 muM 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 alpha7 or alpha4beta2 receptors, which represent the majority of nACh receptors in mammalian brain.