Syntheses, Transformations and Pharmaceutical Applications of Kynurenic Acid Derivatives

Abstract

KEYWORDS: Kynur e ni c acid, Kynure nic acid deriva tive s, Neu rologic al disor d e r s , Schizop h r e n i a , Retinal dam a g e , Diabe t e s mellitus, Hyper t e n s i o n Abstr a c tThe synth e s e s and tran sfo r m a t i o n s of 4-hydroxyq ui n olin e-2-carboxylic acid, kynur e ni c acid, are review e d , and speci al att e n tio n is paid to the phar m a c olo gic al activities and pha r m a c e u t i c al applica tio n s of its derivative s.

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

“…KYNA amides are synthesized by the amidation of KYNA at the carboxyl moiety and the resulting substances may preferentially act on GluN2B subunit-containing extrasynaptic NMDARs [209,309]. 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].…”

Excitotoxic Mechanisms in Non-Motor Dysfunctions and Levodopa- Induced Dyskinesia in Parkinson's Disease: The Role of the Interaction Between the Dopaminergic and the Kynurenine System

“…From this aspect it is of interest to produce synthethic KNYA derivatives which may have more favourable pharmacokinetic properties than those of KYNA, such as an improved receptor selectivity or an improved blood-brain barrier penetration. Several synthethic KYNA analogues have already been developed to achieve neuroprotection 93 .…”

“…The general procedure for the synthesis of 4-hydroxyquinolinic acid can be achieved by a modified Conrad-Limpach method starting from the commercially available substituted aryl amines 1 93,94 . The first step involves enamine bond formation by using dimethyl acetylenedicarboxylate or diethyl acetylenedicarboxylate resulting in 2 (Scheme 1).…”

“…The excellent biological activity of 5 led us to prepare a number of analogues 93,94 . Several of them is shown in Scheme 2.…”

Testing of neuroprotective compounds in a transgenic mouse model of Huntington's disease

“…Accordingly, several new KYNA analogues or prodrugs have been designed (reviewed by Schwarcz, 2004). An important group of these compounds are the KYNA amides (including our novel agent), which are excellent candidates (reviewed by Fulop et al, 2009), because these analogues are known to be capable of the selective inhibition of the NR2B subunit containing NMDA receptors too (Borza et al, 2007). This analogue has already been proved to be beneficial in rat migraine models (applied dose: 300 mg/kg ip; Vamos et al, 2009a;Vamos et al, 2010).…”