Galanthamine

A potent allosteric potentiating ligand of human nAChRs α4β2, α3β4, and α6β4; potentiates agonist responses of the four nAChR subtypes at 0.1-1 uM, acts as an nAChR inhibitor at >10 uM; also shows affinity for chicken/mouse nAChRs α7/5-HT3 in certain areas of the brain; also works as a weak competitive and reversible cholinesterase inhibitor with IC50 of 2.8-3.2 uM; decreases genotoxicity and cell death induced by β-amyloid peptide in SH-SY5Y cell line.Alzheimer's Disease Approved (In Vitro) :Galanthamine inhibits AChE and BChE with IC50 of 0.5 and 8.5 μM. Galanthamine acts as a positive allosteric modulator (PAM) of human α4β2 AChRs expressed in permanently transfected HEK 293 cells. Galanthamine increases the response of (α4β2) 2α5 AChRs to 1 μM ACh by up to 220% with very low concerntration (EC50=0.25 nM) . Only small potentiation (20%) of either α4β2 or (α4β2) 2β3 AChRs is detected using FLEXstation assays. Galanthamine at concentrations of 1 μM and above inhibits all three AChR subtypes. (In Vivo) :Acute administration of Galantamine (0.3-3 mg/kg, i.p.) increases IGF2 mRNA levels in the hippocampus, but not in the prefrontal cortex, in time- and dose-dependent manner. Galantamine (3 mg/kg, i.p.) causes a transient increase in fibroblast growth factor 2 mRNA levels and a decrease in brain-derived neurotrophic factor mRNA levels in the hippocampus, while it does not affect the mRNA levels of other neurotrophic/growth factors. The Galantamine-induced increase in the hippocampal IGF2 mRNA levels is blocked by Mecamylamine, a nonselective nicotinic acetylcholine (ACh) receptor (nAChR) antagonist, and Methyllycaconitine, a selective α7 nAChR antagonist, but not by Telenzepine, a preferential M1muscarinic ACh receptor antagonist. Moreover, the selective α7 nAChR agonist PHA-543613 increasea the IGF2 mRNA levels, while Donepezil, an acetylcholinesterase inhibitor, does not. Galantamine also increases hippocampal IGF2 protein, which is blocked by Methyllycaconitine.