HIFN (2-fluoro-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)nicotinamide) is a synthetic small-molecule agonist of the tropomyosin-related kinase B (TrkB) receptor, designed to mimic brain-derived neurotrophic factor (BDNF) signaling. Structurally, HIFN replaces the six-membered lactam ring of its parent compound HIOC with a fluoropyridine moiety, rendering it achiral and configurationally stable. This modification enhances binding affinity and pharmacokinetic properties.
HIFN activates TrkB by inducing receptor dimerization and phosphorylation, triggering downstream survival pathways (PI3K/Akt, MAPK/Erk). In vitro, HIFN outperforms HIOC in TrkB activation (10 nM concentration) in primary neurons and NIH-3T3-TrkB cells. In vivo, systemic administration of HIFN (30–40 mg/kg) mitigates blast-induced retinal ganglion cell (RGC) degeneration and preserves visual function (contrast sensitivity, acuity) in mice for up to 8 weeks post-injury. Its effects are TrkB-dependent, as co-treatment with the TrkB antagonist ANA-12 abolishes neuroprotection.
HIFN exhibits a critical therapeutic window of ≤3 hours post-injury and dose-dependent efficacy, with no toxicity observed at 600 mg/kg (acute) or 40 mg/kg/day (40-day chronic). Safety assessments reveal no histopathological or biochemical abnormalities in vital organs.
By combining potent TrkB activation, blood-retina barrier penetration, and a robust safety profile, HIFN emerges as a promising therapeutic candidate for traumatic optic neuropathy and broader CNS disorders involving TrkB dysregulation.
