Synthesis and structure-activity relationship of novel pyridyl ethers for the nicotinic acetylcholine receptor.

The preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Variations of the ring size of the azacycle and substitution on the pyridine had dramatic effects on receptor binding affinity with IC50s at the alpha4beta2 nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidinyl)oxy)pyridine 27f with an IC50 of 22 nM.