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 due to their ability to act as substrates for the blood-brain barrier choline transporter.
Crooks
Peter A
PA
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. pcrooks@uky.edu
Ayers
Joshua T
JT
Xu
Rui
R
Sumithran
Sangeetha P
SP
Grinevich
Vladimir P
VP
Wilkins
Lincoln H
LH
Deaciuc
A Gabriela
AG
Allen
David D
DD
Dwoskin
Linda P
LP
D000157:Aconitine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002794:Choline / Q000037:antagonists & inhibitors / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C054634:methyllycaconitine; D009538:Nicotine; D002794:Choline; D004298:Dopamine; D000157:Aconitine