Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

N-n-Alkylation of nicotine converts it from an agonist into an antagonist at neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogues exhibit both high affinity and selectivity at this site, and are able to access the brain...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-04, Vol.14 (8), p.1869-1874
Main Authors: Crooks, Peter A, Ayers, Joshua T, Xu, Rui, Sumithran, Sangeetha P, Grinevich, Vladimir P, Wilkins, Lincoln H, Deaciuc, A.Gabriela, Allen, David D, Dwoskin, Linda P
Format: Article
Language:English
Subjects:
Aconitine - analogs & derivatives
Aconitine - antagonists & inhibitors
Aconitine - metabolism
Animals
Binding Sites
Binding, Competitive - drug effects
Biological and medical sciences
Brain - drug effects
Brain - metabolism
Choline - antagonists & inhibitors
Choline - metabolism
Cholinergic system
Dopamine - metabolism
Ligands
Male
Medical sciences
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Nicotine - antagonists & inhibitors
Nicotine - metabolism
Nicotine - pharmacology
Nicotinic Antagonists - chemistry
Nicotinic Antagonists - pharmacology
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Receptors, Nicotinic - drug effects
Receptors, Nicotinic - metabolism
Structure-Activity Relationship
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Summary:N-n-Alkylation of nicotine converts it from an agonist into an antagonist at neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogues exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood–brain barrier choline transporter. N-n-Alkylation of nicotine converts it from an agonist into an antagonist at neuronal nicotinic receptor subtypes mediating nicotine-evoked dopamine-release. Conformationally restricted analogues exhibit both high affinity and selectivity at this site and are able to access the brain due to their ability to act as substrates for the blood–brain barrier choline transporter.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2003.10.074