TY - JOUR
T1 - 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
AU - Bolchi, Cristiano
AU - Valoti, Ermanno
AU - Gotti, Cecilia
AU - Fasoli, Francesca
AU - Ruggeri, Paola
AU - Fumagalli, Laura
AU - Binda, Matteo
AU - Mucchietto, Vanessa
AU - Sciaccaluga, Miriam
AU - Budriesi, Roberta
AU - Fucile, Sergio
AU - Pallavicini, Marco
PY - 2015/8/27
Y1 - 2015/8/27
N2 - 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. (Figure Presented).
AB - 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. (Figure Presented).
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U2 - 10.1021/acs.jmedchem.5b00904
DO - 10.1021/acs.jmedchem.5b00904
M3 - Article
C2 - 26225816
AN - SCOPUS:84940495347
VL - 58
SP - 6665
EP - 6677
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 16
ER -