Synthesis and structure-activity relationships of pyridine-modified analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543, a potent nicotinic acetylcholine receptor agonist.
Analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, (A-84543, 1) with 2-, 4-, 5-, and 6-substituents on the pyridine ring were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 9,000 nM when tested in vitro for neuronal nicotinic acetylcholine receptor binding activity. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors indicates that pyridine substitution can have a profound effect on efficacy at these subtypes, and several subtype-selective agonists and antagonists have been identified.
Lin
N H
NH
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Gunn
D E
DE
Li
Y
Y
He
Y
Y
Bai
H
H
Ryther
K B
KB
Kuntzweiler
T
T
Donnelly-Roberts
D L
DL
Anderson
D J
DJ
Campbell
J E
JE
Sullivan
J P
JP
Arneric
S P
SP
Holladay
M W
MW
D002460:Cell Line; D006801:Humans; D017136:Ion Transport; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012413:Rubidium / Q000378:metabolism; D013329:Structure-Activity Relationship
C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D012413:Rubidium