Synthesis and Pharmacological Evaluation of α₄β₂ Nicotinic Ligands with a 3‐Fluoropyrrolidine Nucleus

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-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-5-(phenylethynyl)pyridine (11) and 3-((4-fluorophenyl)ethynyl)-5-(((2S,4R)-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.

Fluorine-Containing Prolines: Synthetic Strategies, Applications, and Opportunities

“…Indeed, with the development of novel synthetic methods, a repertoire of fluorinated prolines dramatically increased during the past two decades. It is impossible to consider in this Perspective each individual example in details, but the list of recent bioactive structures with a fragment of fluorinated proline along with a brief description of their application are outlined in Figure . − …”