Octahydropyrrolo[3,4-c]pyrrole: a diamine scaffold for construction of either alpha4beta2 or alpha7-selective nicotinic acetylcholine receptor (nAChR) ligands. Substitutions that switch subtype selectivity.
A series of 5-(pyridine-3-yl)octahydropyrrolo[3,4-c]pyrroles have been prepared that exhibit high affinity to alpha4beta2 and/or alpha7 nicotinic acetylcholine receptors (nAChRs). Simple substitution patterns have been identified that allow construction of ligands that are highly selective for either nAChR subtype. The effects of substitution on subtype selectivity provide some insight into the differences in the ligand binding domains of the alpha4beta2 and alpha7 receptors, especially in regions removed from the cation binding pocket.
Bunnelle
William H
WH
Department R47W, Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois 60064-6117, USA. William.h.bunnelle@abbott.com
Tietje
Karin R
KR
Frost
Jennifer M
JM
Peters
Dan
D
Ji
Jianguo
J
Li
Tao
T
Scanio
Marc J C
MJ
Shi
Lei
L
Anderson
David J
DJ
Dyhring
Tino
T
Grønlien
Jens H
JH
Ween
Hilde
H
Thorin-Hagene
Kirsten
K
Meyer
Michael D
MD
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003959:Diamines / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D003959:Diamines; D008024:Ligands; D018722:Nicotinic Agonists; D011758:Pyrroles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2