Novel analogs of choline as potential neuroprotective agents

Issue title: New Directions in Neuroprotection: Basic Mechanisms, Molecular Targets and Treatment Strategies

Article type: Research Article

Authors: Buccafusco, Jerry J.^{a; b; *} | Beach, J. Warren^{a; c} | Terry, Jr., Alvin V.^{a; c} | Doad, Gurbir S.^c | Sood, Ajay^a | Arias, Esperanza^d | Misawa, Hidemi^e | Masai, Manabu^f | Fujii, Takeshi^f | Kawashima, Koichiro^f

Affiliations: [a] Alzheimer's Research Center, Medical College of Georgia, Augusta, Georgia, USA | [b] Department of Veterans Affairs Medical Center, Augusta, Georgia, USA | [c] Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, USA | [d] Departamento de Farmacologia, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain | [e] Department of Neurology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan | [f] Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan

Correspondence: [*] Corresponding author: Jerry J. Buccafusco, Ph.D., Director, Alzheimer's Research Center, Medical College of Georgia, 1120 – 15th Street, Augusta, Georgia 30912-2300, USA. Tel.: +1 706 721 6355; Fax: +1 706 721 9861; E-mail: [email protected].

Abstract: 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.

Keywords: nicotinic receptor, choline analog, choline uptake, cytoprotection, PC-12 cells, structure-activity

DOI: 10.3233/JAD-2004-6S612

Journal: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S85-S92, 2004