Kynurenic Acid, a Key Endogenous Neuroprotective Agent: Role of Its Derivatives in Therapeutics

Kynurenic acid (KYNA) is an endogenous molecule that acts as a nonselective antagonist of ionotropic glutamate receptors and has been shown to have neuroprotective properties. Although KYNA has shown considerable therapeutic potential in neurodegenerative disorders, its limited permeability across the blood-brain barrier restricts its direct clinical application. To overcome this limitation, various ester and amide derivatives have been developed as prodrugs to enhance brain delivery and subsequently release KYNA within the central nervous system. Beyond serving as prodrugs, KYNA derivatives have attracted substantial interest in medicinal chemistry due to their ability to interact with multiple molecular targets. Additionally, these compounds exhibit a wide range of biological activities, including potential treatments for Alzheimer's disease, Parkinson's disease, Huntington's disease, and psychiatric disorders. Therefore, kynurenic acid-based scaffolds have prompted further research into their derivatives, leading to a range of structurally distinct products. Here, we discuss the neuroprotective role of KYNA and its derivatives, which exhibit diverse bioactivities.