Synthesis and biological effects of some kynurenic acid analogs K. Nagy a,b , I. Plangár b , B. Tuka b , L. Gellért a , D. Varga a , I. Demeter a,b , T. Farkas a , Zs.Kis a , M. Marosi a , D. Zádori b , P. Klivényi b , F. Fülöp c , I. Szatmári c , L. Vécsei b, , J. Toldi a, ⇑ , a Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary b Department of Neurology, University of Szeged, PO Box 427, H-6701 Szeged, Hungary c Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eotvos u.6, Hungary a r t i c l e i n f o Article history: Received 27 July 2011 Accepted 10 October 2011 Available online 18 October 2011 Keywords: Kynurenic acid KYNA amides Synthesis of KYNA amides Neuroprotection Hippocampus Open-field study Electrophysiology a b s t r a c t 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 hydro- chloride (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 effective- ness of these molecules as inhibitors of excitatory synaptic transmission in the CA1 region of the hippo- campus.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 signifi- cant nonspecific general side-effects. KYNA-1 may therefore be considered a promising candidate for clin- ical studies. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction It is well established that excitotoxicity is the hallmark of sev- eral neurodegenerative processes that result from acute events, such as stroke,traumatic brain injury or bacterialmeningitis. 1–4 The background ofthese processes includes an abnormally high glutamate (Glu) level in the brain. In the course of the pathological events,neurons are damaged or killed by the overactivation of receptors ofexcitatory amino acids (EAAs) such as N-methyl-5- D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole- propionic acid (AMPA) and kainate. 5 Glu may also play important roles in the pathogenesis of other brain diseases, for example, Alz- heimer’s disease, Parkinson’s disease, Huntington’s disease, amyo- trophic lateral sclerosis, multiple sclerosis, epilepsy and migraine. 6,7 A reduction of the excitotoxicity, which may be achieved by the blockade of NMDA or other Glu receptors, attenuates some of the pathological symptoms in experimental models of acute and chronic neurodegenerative diseases. 8–11 Although most of the NMDA receptor antagonistsprevent excitotoxicity in cellular and animal models, these drugs have only limited clinical use. A complete NMDA receptor blockade is fre- quently accompanied by side-effects such as psychosis, nausea, vomiting and a memory impairment, which underlines the key role of the NMDA receptors in normal neuronal processes. 12 However, glycine (Gly) and polyamine site agents,NR2B subunit-specific antagonists and ion channel blockers with lower affinity may come into consideration, as they exert attenuated side-effects. 13 Kynure- nic acid (KYNA), an intermediate of the tryptophan metabolism, 14– 16 would be a good candidate, because it is a broad-spectrum endogenousantagonist at ionotropic EAA receptors. 17,18 KYNA inhibits NMDA receptors at the Gly-binding site 19 and it can non- competitively inhibit a7-nicotinic acetylcholine receptors, 20 whereby it can also mediate the inhibition of Glu release in the striatum. 21 However,the use of KYNA as a neuroprotective agent must be excluded because it is barely able to cross the blood–brain barrier (BBB), 22 which rules out its systemic use. This has stimulated the design of several new KYNA analogs, prodrugs or derivatives. 14 A few years ago, we began to create new KYNA amides. 23 These com- pounds are of promise because they are potentially capable of selective inhibition of the NR2B subunit containing NMDA recep- tors. 24 In the present work we have designed and synthesized new KYNA amides which the following structural properties: (1) containing a water-soluble side-chain;(2) containing a new 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.10.029 ⇑ Corresponding author. Tel.: +36 62 544153; fax: +36 63 544291. E-mail address: toldi@bio.u-szeged.hu (J. Toldi). MTA SZTE Neuroscience Research Group. Bioorganic & Medicinal Chemistry 19 (2011) 7590–7596 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry j o u r n a l h omepage: w w w . e l s e v i e r . c o m / l o c a t e / b m c