Synthesis and biological effects of some kynurenic acid analogs

Nagy, K.; Plangár, Imola; Tuka, Bernadett; Gellért, Levente; Varga, Dániel Péter; Demeter, I.; Farkas, Tamás; Kis, Zsolt; Marosi, Máté; Zádori, Dénes; Klivényi, Péter; Fülöp, Ferenc; Szatmári, István; Vécsei, László; Toldi, József

doi:10.1016/j.bmc.2011.10.029

Cited by 30 publications

(41 citation statements)

References 40 publications

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“…In contrast with the electrophysiological findings with KA-1, N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2, Figure 1b) did not decrease, but rather slightly increased the amplitudes of field excitatory postsynaptic potentials (fEPSPs) (Nagy et al, 2011). However, in a recent study, pretreatment with KA-2 was also able to attenuate the effects of nitroglycerine (NTG) in an experimental model of migraine (Fejes-Szabó et al, 2014).…”

Section: Introductionmentioning

confidence: 42%

“…With regard to in vitro electrophysiology studies, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-1, Figure 1a) has been demonstrated to be an even more effective inhibitor of hippocampal excitatory synaptic transmission than KYNA (Nagy et al, 2011). Accordingly, in an in vivo model of trigeminal activation, KA-1 displayed better efficacy than that of its parent compound, KYNA (Knyihar-Csillik et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study

et al. 2016

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Abstract:Kynurenic acid (KYNA) has well-established protective properties against glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during headache disorders. The goal of this study was to Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationcompare the effects of two KYNA analogs, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-1) and N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2), in the orofacial formalin test of trigeminal pain. Following pretreatment with KA-1 or KA-2, rats were injected with subcutaneous formalin solution in the right whisker pad. Thereafter, the rubbing activity and c-Fos immunoreactivity changes in the spinal trigeminal nucleus pars caudalis (TNC) were investigated. To obtain pharmacokinetic data, KA-1, KA-2 and KYNA concentrations were measured following KA-1 or KA-2 injection. Behavioral tests demonstrated that KA-2 induced a larger amelioration of formalin-evoked alterations as compared with KA-1 and the assessment of c-Fos immunoreactivity in the TNC yielded similar results. Although KA-1 treatment resulted in approximately four times larger area under the curve values in the serum relative to KA-2, the latter resulted in a higher KYNA elevation than in the case of KA-1. With regard to TNC, the concentration of KA-1 was under the limit of detection, while that of KA-2 was quite small and there was no major difference in the approximately 10-fold KYNA elevations. These findings indicate that the differences between the beneficial effects of KA-1 and KA-2 may be explained by the markedly higher peripheral KYNA levels following KA-2 pretreatment. Targeting the peripheral component of trigeminal pain processing would provide an option for drug design which might prove beneficial in headache conditions. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationReviewer #2: The Authors have tried to address the comments of the referees and partially improved the manuscript. Some issues still need improvement.The sentence 'glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during headache disorders' is incorrect. This statement may be true for some primary headaches (migraine and chronic migraine), but not for 'headaches' in general.The sentence was modified accordingly.The way the data are presented is still quite confusing:Description of the time boundaries for Phase I and II is missing in the Methods section. The Methods section was supplemented with the requested information.A Figure ( Table 1 reports the levels of significance for data presented in Figure 2: the table should be inglobated in said figure otherwise the reader is forced to go back and forth.The requested modification was done in Figure 2 and Table 1 was removed. Table 2 should be associated to a figure that illustrates mean+sd of time spent in rubbing during the 2 phases of formalin in the di...

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Section: Introductionmentioning

confidence: 42%

Section: Introductionmentioning

confidence: 99%

A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study

et al. 2016

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“…Accordingly, one of the KYNA amide compounds synthesized by our group, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride exerted protective effects both in the N171-82Q transgenic mouse model of Huntington's disease and the four-vessel occlusion model of cerebral ischemia in rats [310,311]. At the dose capable of exerting these neuroprotective effects, the KYNA analog did not demonstrate any significant systemic side effects, i.e., it did not alter locomotor activity, working memory performance, and long-lasting, consolidated reference memory in contrast to the observed indirect side-effects following KYN administration [312][313][314]. These results are supported by the findings that instead of decreasing LTP as it might be expected from its potential NMDAR antagonistic properties, it rather facilitated the potentiation of field excitatory postsynaptic potentials [315].…”

Section: Kynurenic Acidmentioning

confidence: 82%

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Zádori

Veres

Szalárdy

et al. 2018

JAD

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The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathwayrelated alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.3

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“…SZR72 definitely decreased the amplitudes of the fEPSPs evoked at low frequency prior to LTP induction. This might be ascribed to the fact that KYNA can barely penetrate the BBB [6], whereas SZR72 traverses the BBB much more effectively [20].…”

Section: Discussionmentioning

confidence: 99%

Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study

Demeter

Nagy

Farkas

et al. 2013

Neuroscience Letters

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Synthesis and biological effects of some kynurenic acid analogs

Cited by 30 publications

References 40 publications

A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study

A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study

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