title: Synthesis and biological effects of some kynurenic acid analogs.
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.
authors.affiliation: Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Nagy
authors.forename: I
authors.initials: I
authors.lastname: Plangár
authors.forename: B
authors.initials: B
authors.lastname: Tuka
authors.forename: L
authors.initials: L
authors.lastname: Gellért
authors.forename: D
authors.initials: D
authors.lastname: Varga
authors.forename: I
authors.initials: I
authors.lastname: Demeter
authors.forename: T
authors.initials: T
authors.lastname: Farkas
authors.forename: Zs
authors.initials: Z
authors.lastname: Kis
authors.forename: M
authors.initials: M
authors.lastname: Marosi
authors.forename: D
authors.initials: D
authors.lastname: Zádori
authors.forename: P
authors.initials: P
authors.lastname: Klivényi
authors.forename: F
authors.initials: F
authors.lastname: Fülöp
authors.forename: I
authors.initials: I
authors.lastname: Szatmári
authors.forename: L
authors.initials: L
authors.lastname: Vécsei
authors.forename: J
authors.initials: J
authors.lastname: Toldi
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D055724:Electrophysiological Phenomena; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000577:Amides; D018691:Excitatory Amino Acid Antagonists; D007736:Kynurenic Acid