Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as alpha4beta2-Nicotinic Acetylcholine Receptor Agonists

Some unichiral analogues of 2R,2?S-2-(1?-methyl-2?-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective ?4?2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high ?4?2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High ?4?2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known ?4?2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the ?4?2 and ?3?4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are ?4?2 full agonists, but only the latter is highly ?4?2/?3?4 selective, while potent and selective partial ?4?2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues. (Figure Presented).