SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood-Brain Barrier.

Kinga Molnár,Imola Wilhelm,László Vécsei,István Ilisz,Noémi Kmetykó,Bálint Lőrinczi,István A Krizbai,Róbert Berkecz,Csilla Fazakas,Ferenc Fülöp,István Szatmári

doi:10.3390/pharmaceutics13010061

Abstract

By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood–brain barrier. One possibility to overcome this problem is to use analogues with similar biological activity as kynurenic acid, but with an increased permeability through the blood–brain barrier. We synthesized six novel aminoalkylated amide derivatives of kynurenic acid, among which SZR-104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide) proved to have the highest permeability through an in vitro blood–brain barrier model. In addition, permeability of SZR-104 was significantly higher than that of kynurenic acid, xanthurenic acid and 39B, a quinolone derivative/xanthurenic acid analogue. Since peripherally administered SZR-104 is able to inhibit epileptiform activity in the brain, we conclude that SZR-104 is a promising kynurenic acid analogue with good penetrability into the central nervous system.

Highlights

The kynurenine (KYN) pathway plays an important role in the production of nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP+) and other notable compounds from the cleavage of tryptophan (Trp) [1]
An increasing amount of data regarding KYN metabolites suggests their indisputable role in neurophysiological diseases, such as ischaemia, headache, schizophrenia, epilepsy, Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS)
Through the use of different secondary amines and morpholine, we aimed to investigate the blood–brain barrier (BBB) penetration altering effect of the aminoalkyl function formed during the modified Mannich reactions

Summary

Introduction

The kynurenine (KYN) pathway plays an important role in the production of nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADP+) and other notable compounds from the cleavage of tryptophan (Trp) [1]. As a result of this diverse, multiple branched cleavage pathway, 95% of Trp is converted into kynurenic acid (KYNA) (Figure 1). By being a non-competitive antagonist at the glycine site of glutamatergic N-methyl-D-aspartate (NMDA) receptor, KYNA is able to decrease excitotoxicity and serves as an endogenous neuroprotectant. KYNA is a weak antagonist on kainate and α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) glutamatergic and a few other receptors. KYNA acts as a free radical scavenger. All these effects complement the potent neuroprotective profile of KYNA [2]. An increasing amount of data regarding KYN metabolites suggests their indisputable role in neurophysiological diseases, such as ischaemia, headache, schizophrenia, epilepsy, Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS)

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