Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer's disease

Cholinesterase inhibitors are the only approved drug treatment for patients with mild to moderately severe Alzheimer's disease, interestingly the clin ical potency of these drugs does not correlate well with their. activity as cholinesterase inhibitors, nor is their action, as short lived as would be expected from purely symptomatic treatment. A few cholinesterase inhibitor s, including galantamine, produce beneficial effects even after drug treatm ent has been terminated. These effects assume modes of action other than me re esterase inhibition and are capable of inducing systemic changes. We hav e recently discovered a mechanism that could account at least in part, for the above-mentioned unexpected properties of some some cholinesterase inhib itors. We have Sound that a subgroup of cholinesterase inhibitors, includin g galantamine but excluding tacrine, directly interacts with nicotinic acet ylcholine receptors, These compounds, named allosterically potentiating lig ands, sensitize nicotinic receptors by increasing the probability of channe l opening induced by acetylcholine and nicotinic agonists and by slowing do wn receptor desensitization. The allosterically potentiating ligand action, which is not necessarily associated with cholinesterase inhibition, has be en demonstrated by whole-cell patch-clamp recordings to occur in natural mu rine and human neurons and in murine and human cell lines expressing variou s subtypes of neuronal nicotinic acetylcholine receptors. (C) 2001 Society of Biological Psychiatry.