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Synthesis and Pharmacological Evaluation of α 4 β 2 Nicotinic Ligands with a 3‐Fluoropyrrolidine Nucleus
Author(s) -
Tamborini Lucia,
Pinto Andrea,
Ettari Roberta,
Gotti Cecilia,
Fasoli Francesca,
Conti Paola,
De Micheli Carlo
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500073
Subject(s) - pyridine , chemistry , nicotinic agonist , pyrrolidine , stereochemistry , selectivity , nucleus , nicotinic acetylcholine receptor , receptor , neuroscience , medicinal chemistry , biochemistry , biology , catalysis
Abstract Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer’s and Parkinson’s diseases, schizophrenia, and mood disorders. The α 4 β 2 subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer’s disease symptoms. Herein we report a new class of α 4 β 2 receptor ligands characterized by a basic pyrrolidine nucleus, the basicity of which was properly decreased through the insertion of a fluorine atom at the 3‐position, and a pyridine ring carrying at the 3‐position substituents known to positively affect affinity and selectivity toward the α 4 β 2 subtype. Derivatives 3‐(((2 S ,4 R )‐4‐fluoropyrrolidin‐2‐yl)methoxy)‐5‐(phenylethynyl)pyridine ( 11 ) and 3‐((4‐fluorophenyl)ethynyl)‐5‐(((2 S ,4 R )‐4‐fluoropyrrolidin‐2‐yl)methoxy)pyridine ( 12 ) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α 4 β 2 subtype and physicochemical properties predictive of a relevant central nervous system penetration.