Synthesis and biological effects of some kynurenic acid analogs

K. Nagy, I. Plangár, B. Tuka, L. Gellért, D. Varga, I. Demeter, T. Farkas, Z. Kis, M. Marosi, D. Zádori, P. Klivényi, F. Fülöp, I. Szatmári, L. Vécsei, J. Toldi

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The overactivation of excitatory amino acid receptors plays a key role in the pathomechanism of several neurodegenerative disorders and in ischemic and post-ischemic events. Kynurenic acid (KYNA) is an endogenous product of the tryptophan metabolism and, as a broad-spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The use of KYNA is excluded, however, because it hardly crosses the blood-brain barrier. Accordingly, new KYNA analogs which can readily cross this barrier and exert their complex anti-excitatory activity are generally needed. During the past 6 years, we have developed several KYNA derivatives, among others KYNA amides. These new analogs included one, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H- quinoline-2-carboxamide hydrochloride (KYNA-1), that has proved to be neuroprotective in several models. This paper reports on the synthesis of 10 new KYNA amides (KYNA-1-KYNA-10) and on the effectiveness of these molecules as inhibitors of excitatory synaptic transmission in the CA1 region of the hippocampus. The molecular structure and functional effects of KYNA-1 are compared with those of other KYNA amides. Behavioral studies with these KYNA amides demonstrated that they do not exert significant nonspecific general side-effects. KYNA-1 may therefore be considered a promising candidate for clinical studies.

Original languageEnglish
Pages (from-to)7590-7596
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number24
DOIs
Publication statusPublished - Dec 15 2011

Fingerprint

Kynurenic Acid
Amides
Glutamate Receptors
Protective Agents
Nervous System Diseases
Molecular Structure
Blood-Brain Barrier
Metabolism
Synaptic Transmission
Tryptophan
Neurodegenerative Diseases
Molecular structure

Keywords

  • Electrophysiology
  • Hippocampus
  • KYNA amides
  • Kynurenic acid
  • Neuroprotection
  • Open-field study
  • Synthesis of KYNA amides

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Nagy, K., Plangár, I., Tuka, B., Gellért, L., Varga, D., Demeter, I., ... Toldi, J. (2011). Synthesis and biological effects of some kynurenic acid analogs. Bioorganic and Medicinal Chemistry, 19(24), 7590-7596. https://doi.org/10.1016/j.bmc.2011.10.029

Synthesis and biological effects of some kynurenic acid analogs. / Nagy, K.; Plangár, I.; Tuka, B.; Gellért, L.; Varga, D.; Demeter, I.; Farkas, T.; Kis, Z.; Marosi, M.; Zádori, D.; Klivényi, P.; Fülöp, F.; Szatmári, I.; Vécsei, L.; Toldi, J.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 24, 15.12.2011, p. 7590-7596.

Research output: Contribution to journalArticle

Nagy K, Plangár I, Tuka B, Gellért L, Varga D, Demeter I et al. Synthesis and biological effects of some kynurenic acid analogs. Bioorganic and Medicinal Chemistry. 2011 Dec 15;19(24):7590-7596. https://doi.org/10.1016/j.bmc.2011.10.029
Nagy, K. ; Plangár, I. ; Tuka, B. ; Gellért, L. ; Varga, D. ; Demeter, I. ; Farkas, T. ; Kis, Z. ; Marosi, M. ; Zádori, D. ; Klivényi, P. ; Fülöp, F. ; Szatmári, I. ; Vécsei, L. ; Toldi, J. / Synthesis and biological effects of some kynurenic acid analogs. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 24. pp. 7590-7596.
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