Synthesis and biological characterization of 4,4-difluoro-3-(phenoxymethyl)piperidine scaffold as dopamine 4 receptor (D4R) antagonist in vitro tool compounds

We report the discovery and characterization of a novel series of 4,4-difluoropiperidine ether-based dopamine D4 receptor antagonists. Structure-activity relationship studies led to the identification of compound 14a, which displays exceptional binding affinity for the D4 receptor (Ki = 0.3 nM) and remarkable selectivity over other dopamine receptor subtypes (>2000-fold versus D1, D2, D3, and D5). However, compounds in this series were shown to have poor microsomal stability and high plasma protein binding. Despite these limitations, the exceptional selectivity profile of these compounds makes them valuable tool compounds for investigating D4 receptor signaling in cellular models of L-DOPA-induced dyskinesias. These findings provide important structural insights for the future development of metabolically stable D4 receptor antagonists for therapeutic applications.