Synthesis and Pharmacological Evaluation of α4β2 Nicotinic Ligands with a 3‐Fluoropyrrolidine Nucleus. Issue 6 (16th April 2015)

• Record Type: Journal Article
• Authors: Tamborini, Lucia; Pinto, Andrea; Ettari, Roberta; Gotti, Cecilia; Fasoli, Francesca; Conti, Paola; De Micheli, Carlo
• Is Part Of: ChemMedChem. Volume 10:Issue 6(2015:Jun.)
• Page Start: 1071
• Page End: 1078
• Publication Date: 2015-04-16
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500073
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 α₄β₂ 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 α₄β₂ 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 α₄β₂ subtype. Derivatives 3‐(((2<italic>S</italic>, 4<italic>R</italic>)‐4‐fluoropyrrolidin‐2‐yl)methoxy)‐5‐(phenylethynyl)pyridine (<bold>11</bold>) and 3‐((4‐fluorophenyl)ethynyl)‐5‐(((2<italic>S</italic>, 4<italic>R</italic>)‐4‐fluoropyrrolidin‐2‐yl)methoxy)pyridine (<bold>12</bold>) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α₄β₂ subtype and physicochemical properties predictive of a relevant central nervous system penetration.</p> </abstract>