Synthesis and structure-activity relationships of pyridine-modified analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543, a potent nicotinic acetylcholine receptor agonist

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

“…Affinity values (K i , nanomolar) are based on inhibition of ligand binding to nicotinic (α 4 β 2 /α 3 β * 4 /α 7 ) receptors. Values selected from the following: Abreo et al, 1996;Cosford et al, 1996;Holladay et al, 1998a,b;Koren et al, 1997;Krow et al, 2000a;Lin et al, 1997Lin et al, , 1998Lin et al, , 1999Lin et al, , 2001Lin et al, , 2002. Both enantiomers of SIB-1508Y (S > R) are active in functional assays with potencies in the following order: α 4 β 2 , α 4 β 2 , α 3 β 2 > α 3 β 4 α 7 (Cosford et al, 1996).…”

QSAR study of a large set of 3-pyridyl ethers as ligands of the α4β2 nicotinic acetylcholine receptor

“…One hundred and fifty-eight diverse pyridyl ether analogues were taken from several published works [10][11][12][13][38][39][40][41][42][43][44]. Our study was based on two fundamental Fig.…”

“…Currently, the analogues of A-85380 (3-pyridyl ethers analogues) have been becoming the focus in the development of nAChR ligands. A large diversity of 3-pyridyl ether analogues have been synthesized based on bioisosteric substitution in the past decades [10][11][12][13][14][15][16][17]. Some of them evenly obtained an affinity at pM magnitude.…”

Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

“…Members of this class are, for instance, ABT-089 (22), which is in Phase I for Alzheimer's disease in USA, and ABT-594 (23), which is in Phase II clinical trial as analgesic. It has been studied 74 how the substitution in the various positions of the pyridine ring can influence affinity, selectivity and efficacy. Compound 24a (X ¼ 4-Me, K i 4.12 nM) was a partial agonist on the human a4b2 subtype, but it showed no activity on the ganglionic-type a3bx receptor, while 24b (X ¼ 5-n-C 3 H 7 , K i 0.16 nM) showed antagonistic properties, on both subtypes, with different potency.…”

“…It has been shown how small changes in the chemical structure may shift activity from agonist to antagonist: for instance, compound 24c (Fig. 5, X ¼ 5-Me) stimulates cation efflux in K177 cells while 24c (X ¼ 5-n-Pr), which differs only for two carbon units, blocks it; 74 compound 25c (Fig. 5, R ¼ 3-pyridyl) has antagonistic properties on IMR32 cells expressing a3bx receptor, while 25b (R ¼ 5-pyrimidinyl) is a partial agonist in the same preparation.…”