GAMBOGIC AMINE, A SELECTIVE TrkA AGONIST WITH NEUROPROTECTIVE ACTIVITY

摘要

Small molecule agonists, partial agonists, and antagonists for the TrkA receptor are described. The compounds are gambogic amines, where the carboxylic acid group of gambogic acid (CO₂H) has been replaced by an amine group (CH₂NR₁R₂). In some embodiments, the compounds selectively bind to TrkA but not TrkB or C, robustly induce its tyrosine phosphorylation and downstream signaling activation including Akt and MAP kinases. Further, they can strongly prevent glutamate-induced neuronal cell death and provoke prominent neurite outgrowth in PC12 cells. Gambogic amines specifically interact with the cytoplasmic juxtamembrane domain of TrkA receptor and trigger its dimerization. Administration of these compounds in can substantially diminishes Kainic acid-triggered neuronal cell death and decrease infarct volume in transient middle cerebral artery occlusion (MCAO) model of stroke. Thus, these compounds can provide effective treatments for debilitating neurodegenerative diseases and provide neuroprotection from patients suffering from stroke or other ischemic events.