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 α4β2-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 α4β2-nAChR partial agonist, were
designed by opening dioxane and replacing hydroxyl carbon with nitrogen.
The resulting 3-pyridyl and m-hydroxyphenyl ethers
have high α4β2 affinity and good subtype selectivity,
which get lost if OH is removed from phenyl or the position of pyridine
nitrogen is changed. High α4β2 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
α4β2 agonists, although the interaction mode of the aryloxymethylene
substructure cannot be assimilated to that of benzodioxane. Indeed,
the α4β2 and α3β4 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 α4β2 full agonists, but only the latter is highly
α4β2/α3β4 selective, while potent and selective
partial α4β2 agonism characterizes the hydroxybenzodioxane
derivative and its two opened semirigid analogues.