Characterization of the Effects of L-4-Chlorokynurenine on Nociception in Rodents


      • The NMDA receptor (NMDAR) is regulated by the glycineB-site (GlyB).
      • 4-Cl-kynurenine (AV-101) is a prodrug that does not bind to the NMDAR GlyB.
      • AV-101 metabolite, 7-Cl-kynurenic acid, is a potent NMDAR GlyB antagonist.
      • Brain 7-Cl-kynurenic acid concentrations achieved exceed the IC50 of GlyB.
      • AV-101 reduces tissue/nerve injury pain with minimal adverse effects.


      Upon systemic administration in rats, the prodrug L-4-chlorokynurenine (4-Cl-KYN; AV-101; VistaGen Therapeutics, Inc, South San Francisco, CA) is rapidly absorbed, actively transported across the blood-brain barrier, and converted in astrocytes to 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine B coagonist site of the N-methyl-D-aspartate (NMDA) receptor. We examined the effects of 4-Cl-KYN in several rat models of hyperalgesia and allodynia and determined the concentrations of 4-Cl-KYN and newly produced 7-Cl-KYNA in serum, brain, and spinal cord. Adult male rats were given 4-Cl-KYN (56, 167, 500 mg/kg), the NMDA receptor antagonist MK-801 (.1, .3, 1.0 mg/kg), or gabapentin (33, 100, 300 mg/kg) intraperitoneally, and were then examined on rotarod, intraplantar formalin-evoked flinching, thermal escape in the normal and carrageenan-inflamed paw, and allodynia after sciatic nerve ligation. Our conclusions show that after systemic delivery, the highest 2 doses (167 and 500 mg/kg) of 4-Cl-KYN yielded brain concentrations of 7-Cl-KYNA exceeding its half maximal inhibitory concentration (IC50) at the glycine B site and resulted in dose-dependent antihyperalgesia in the 4 models of facilitated processing associated with tissue inflammation and nerve injury. On the basis of the relative dose requirements for analgesic actions and side effect profiles from these experiments, 4-Cl-KYN is predicted to have antihyperalgesic efficacy and a therapeutic ratio equal to gabapentin and superior to MK-801.


      These studies show that systemic administration of the prodrug 4-Cl-KYN produces high central nervous system levels of 7-Cl-KYNA, a potent and highly selective antagonist of the NMDA receptor. Compared with other drugs tested, 4-Cl-KYN has robust antinociceptive effects with a better side effect profile, highlighting its potential for treating hyperpathic pain states.

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