title: Synthesis and structure-activity relationships of pyridine-modified analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543, a potent nicotinic acetylcholine receptor agonist.
abstract: 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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Lin
authors.forename: D E
authors.initials: DE
authors.lastname: Gunn
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.forename: H
authors.initials: H
authors.lastname: Bai
authors.forename: K B
authors.initials: KB
authors.lastname: Ryther
authors.forename: T
authors.initials: T
authors.lastname: Kuntzweiler
authors.forename: D L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: J E
authors.initials: JE
authors.lastname: Campbell
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: S P
authors.initials: SP
authors.lastname: Arneric
authors.forename: M W
authors.initials: MW
authors.lastname: Holladay
mesh_terms: 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
chemical_list: C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D012413:Rubidium