Synthesis and in vitro evaluation of galanthamine derivatives for examination of nicotinic acetylcholine receptor system

ISunmrary: The syntheses and radioactive labeling of several galanthamine derivatives, 6-O-demethyl-6-O-fluoroethylgalanthamine, 10-N-demethyl-lO-Nfluoroethylgalanthamine and N-methylgalanthaminium are reported. First ill vitro evaluations were carried out to determine their properties as allosterically potentiating ligands of nicotinic receptors. N-methylgalanthaminium was found to be a promising candidate for further investigations. The most commonly applied therapeutic approach to balance nicotinic cholinergic deficits in Alzheimer’s disease (AD) patients is the administration of acetylcholinesterase inhibitors (AChE-I) although they have been proven to be of limited therapeutic value [ 13, A novel approach to drug treatment in AD is the application of allosterically potentiating ligands (APL) acting on nicotinic acetylcholine receptors (nAChR). APLs interact with the receptor via binding sites that are distinct from those for nicotinic agonists and antagonists. They also up-modulate the channel activity of nAChRs in response to acetylcholine (ACh) and other nicotinic agonists [2]. Representative members of this class of ligands are the plant alkaloids physostigmine, codeine and galhhamine.