title: Novel analogs of choline as potential neuroprotective agents.
abstract: The ability of choline to serve as a full, though low potency agonist for the alpha7 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 [(3)H]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 approximately 30 nM) cytoprotective action that was blocked by pretreatment with the alpha7 nicotinic receptor selective antagonist methyllycaconitine, but not by thealpha2 subtype-preferring antagonist dihydro-beta-erythroidin. These preliminary studies support the further neurochemical characterization of these compounds 1) as selectivealpha7 nicotinic receptor agonists and, 2) based on their interaction with the choline transporter, as potential cholinergic false neurotransmitters as has been demonstrated for pyrrolidinecholine.
authors.affiliation: Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912, USA. jbuccafu@mcg.edu
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Buccafusco
authors.forename: J Warren
authors.initials: JW
authors.lastname: Beach
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Gurbir S
authors.initials: GS
authors.lastname: Doad
authors.forename: Ajay
authors.initials: A
authors.lastname: Sood
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arias
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Masai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujii
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kawashima
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002794:Choline / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006736:Horses; D006801:Humans; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects
chemical_list: D004983:Ethanolamines; C501054:N-(3-fluorobenzyl)-N-methylethanolamine; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D002794:Choline; D000157:Aconitine