HIOC Derivatives for the Treatment of Trauma-Induced Vision Loss
Abstract
Pressure waves due to explosions can damage the neurons of the eye and visual centers in the brain, leading to visual function loss. There are currently few treatments for such injuries that can be deployed rapidly in the field to mitigate such damage. We have developed small molecule activators of TrkB, the cognate receptor for brain-derived neurotrophic factor (BDNF), which cross the blood/retina and blood/brain barriers. Based on a preliminary lead compound, N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC), we synthesized and tested the biological activity of 28 derivatives. At least two analogs have TrkB activation potency that is clearly superior to HIOC. Our best candidate is 2-fluoro-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)nicotinamide (HIFN), which protects against blast-induced loss of visual function in a small animal model, when injected at a maximally effective dose of 30 mg/kg within three hours of trauma. HIFN exhibits no detectable acute or chronic toxicity in treated animals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1210504
Entities
People
- Frank E. Mcdonald
- Paul M. Iuvone
Organizations
- Emory University