Abstract
The mammalian kynurenine aminotransferase (KAT) enzymes are a family of related isoforms that are pyridoxal 5’-phosphate-dependent, responsible for the irreversible transamination of kynurenine to kynurenic acid. Kynurenic acid is implicated in human diseases such as schizophrenia where it is found in elevated levels and consequently KAT-II, as the isoform predominantly responsible for kynurenic acid production in the brain, has been targeted for the development of specific inhibitors. One class of compounds that have also shown inhibitory activity towards the KAT enzymes are estrogens and their sulfate esters. Estradiol disulfate in particular is very strongly inhibitory and it appears that the 17-sulfate makes a significant contribution to its potency. The work here demonstrates that the effect of this moiety can be mirrored in existing KAT-II inhibitors, from the development of two novel inhibitors, JN-01 and JN-02. Both inhibitors were based on NS-1502 (IC50: 315 μM), but the deliberate placement of a sulfonamide group significantly improved the potency of JN-01 (IC50: 73.8 μM) and JN-02 (IC50: 112.8 μM) in comparison to the parent compound. This 3–4 fold increase in potency shows the potential of these moieties to be accommodated in the KAT-II active site and the effect they can have on improving inhibitors, and the environments in the KAT-II have been suitably modelled using docking calculations.
Highlights
Kynurenic acid (KYNA) is a metabolite formed in the kynurenine pathway of tryptophan catabolism (Fig 1), produced when kynurenine is irreversibly transaminated into KYNA by the kynurenine aminotransferase (KAT) enzymes [1]
For the design approach to improving this inhibitor, we took the core of NS-1502 and strategically mimicked sulfated estrogens when synthesising JN-01
KAT-II inhibitors have been shown to reduce the production of KYNA, increase neurotransmitter release and improve memory tasks in animals [12, 13, 17]
Summary
Kynurenic acid (KYNA) is a metabolite formed in the kynurenine pathway of tryptophan catabolism (Fig 1), produced when kynurenine is irreversibly transaminated into KYNA by the kynurenine aminotransferase (KAT) enzymes [1]. KYNA is an antagonist of the glycine and glutamate binding sites of NMDA receptors [2, 3], the α-amino-3-hydroxy-5-methyl4-isoxazole propionic acid (AMPA) receptor [4], and kainate receptors [5]. By inhibiting the activity of these glutamatergic receptors and preventing excitotoxic attacks, as well as diverting the pathway from the formation of neurotoxic metabolites (such as 3-hydroxykynurenine and quinolinic acid), KYNA can be considered neuroprotective. April 24, 2018 provides support for author GS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section
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