Identification of N-(Alkyl)-4-phenylpiperidines as Anti-Neuroinflammatory Agents

Neuroinflammation is increasingly recognized as an important pathological feature in numerous disorders of the CNS, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. Many of the drugs used to treat CNS diseases display immunomodulatory properties. In this study, we demonstrate N-(alkyl)-4-arylpiperidine, a derivative of which is commonly found in CNS drugs, is an anti-neuroinflammatory pharmacophore. A series of N-(alkyl)-4-phenylpiperidines were evaluated for ability to suppress LPS-induced IL-6 levels in BV2 microglial cells. Several of these molecules showed activity and the results generated allowed for the delineation of a structure-activity trend and identified lead compound 4b. Further studies showed 4b suppressed various inflammatory mediators in BV2 cells, primary microglia, and T cells, including IL-6, TNF, IL-1β, and NO. Mechanistic studies demonstrated modulation of the NF-κB pathway as a potential mechanism of action. Taken together, our work shows N-(alkyl)-4-phenylpiperidines possess broad anti-neuroinflammatory activity and have potential in treating CNS disorders.