Novel analogs of choline as potential neuroprotective agents

The ability of choline to serve as a full, though low potency agonist for the α7 nicotinic receptor has provided the impetus to develop analogs that exhibit levels of potency and effectiveness suitable for use as therapeutic agents. Seven analogs of choline were synthesized based on previous work with the analog pyrrolidinecholine. The drugs were administered to differentiated PC-12 cells 24 hr prior to growth factor withdrawal which itself induced cytotoxicity in 30-40% of the cells. Three of 7 choline analogs exhibited potency and efficacy similar to that for nicotine as cytoprotective agents. Despite being tertiary amines, 4 of the choline analogs were more potent than choline in inhibiting [³H]choline uptake into cultured fibroblasts transfected with the high affinity, sodium-dependent choline transporter. One of the most effective analogs JAY 2-21-29 was shown to produce a potent (EC50 ∼ 30 nM) cytoprotective action that was blocked by pretreatment with the α7 nicotinic receptor selective antagonist methyllycaconitine, but not by theα2 subtype-preferring antagonist dihydro-β-erythroidin. These preliminary studies support the further neurochemical characterization of these compounds 1) as selectiveα7 nicotinic receptor agonists and, 2) based on their interaction with the choline transporter, as potential cholinergic false neurotransmitters as has been demonstrated for pyrrolidinecholine.