Kainic Acid Analogues Research Articles

Kainic Acid-Based Agonists of Glutamate Receptors: SAR Analysis and Guidelines for Analog Design

A comprehensive survey of kainic acid analogs that have been tested for their biological activity is presented. Specifically, this review (1) gathers and compares over 100 kainoids according to a relative activity scale, (2) exposes structural features required to optimize affinity for kainate receptors, and (3) suggests design rules to create next-generation KA analogs. Literature SAR data are analyzed systematically and combined with the most recent crystallographic studies. In view of the renewed interest in neuroactive molecules, this review aims to help guide the efforts of organic synthesis laboratories, as well as to inform newcomers to KA/GluK research.

Characterization of novel kainic acid analogs as inhibitors of select microglial functions

Alzheimer's disease (AD) is characterized by abnormal accumulation of extracellular amyloid beta protein (Aβ) plaques and intracellular neurofibrillary tangles, as well as by a state of chronic inflammation in the central nervous system (CNS). Adverse activation of microglia, the brain immune cells, is believed to contribute to AD pathology including excessive neuronal death. Thus, normalizing immune functions of microglia could slow neurodegeneration, and identification of novel compounds capable of modifying microglial functions is an important goal. Since kainic acid (KA) has been shown to modulate microglial morphology and immune functions, we synthesized six new KA analogs (KAAs) and tested their effects on select microglial functions by using three different cell types as microglia models. Four of the KAAs at low micromolar concentrations inhibited secretion of cytotoxins, monocyte chemoattractant protein (MCP)−1, reactive oxygen species and nitric oxide (NO) by immune-stimulated microglia-like cells. We hypothesize that the effects of the novel KAAs on microglia-like cells are not mediated by KA receptors since their biological activity was distinct from that of KA in all assays performed. A structural similarity search identified aldose reductase (AR) as a potential target for the novel KAAs. This hypothesis was supported by use of AR inhibitor zopolrestat, which abolished the inhibitory effects of two KAAs on microglial secretion of NO. Since the newly developed KAAs inhibited pro-inflammatory and cytotoxic functions of microglia, they should be further investigated for their potential beneficial effect on neuroinflammation and neurodegeneration in AD animal models.

Synthesis of Kainoids and C4 Derivatives.

A unified stereoselective synthesis of 4-substituted kainoids is reported. Four kainic acid analogues were obtained in 8-11 steps with up to 54% overall yields. Starting from trans-4-hydroxy-l-proline, the sequence enables a late-stage modification of C4 substituents with sp2 nucleophiles. Stereoselective steps include a cerium-promoted nucleophilic addition and a palladium-catalyzed reduction. A 10-step route to acid 21a was also established to enable ready functionalization of the C4 position.

Synthesis and biological evaluation of (-)-kainic acid analogues as phospholipase D-coupled metabotropic glutamate receptor ligands.

(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues 1a-c were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate 5a followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative 1c retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of 1c by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound 14 which retained robust agonism at 1 μM and appears to be suitable for future use in pull-down assays and far western blotting for PLD-mGluR isolation.

Efficient synthesis of kainic acid analogues

The present paper deals with an improved synthesis of two molecular hybrids of AMPA and KA, compounds CIP-A and CIP-B, and their transformation into CIOP-A and CIOP-B, the corresponding amido derivatives. Exploiting the continuous-flow technology, a significant improvement in the synthesis of the glutamate agonists CIP-A and CIP-B was accomplished, in terms of overall yield, time, and excess of ethyl chlorooximinoacetate. Moreover, we find out the HPLC conditions suitable to separate, at a preparative level, the three intermediates formed in the 1,3-dipolar cycloaddition step.

Synthesis of Novel Haptens and Conjugates for Antibody Production against Kainoid Family

Amnesic shellfish poisoning (ASP) is caused by consumption of contaminated seafood that has accumulated kainic acid or kainoid analogues such as domoic acid. Among the different ASP bioassays, immunoassays are an attractive alternative to the in vivo mouse bioassay. Herein, we report the synthesis and bioconjugation of two new haptens for the generation of a specific antibody against members of the kainoid family.

Synthesis of both epimeric triacid ananlogs of kainic acid

A practical and cheap method for synthesis of C-4 carboxylic acid substituted kainic acid analogue 5 and its epimer 6 from trans-4-hydroxyproline is described. Using this method, more interesting intermediates and analogues could be obtained easily.

A novel photoaffinity ligand for kainate sites labels two polypeptides with molecular mass 45 and 33.5 kDa in chick cerebellum.

The synthesis of (2S,3S,4S)-4-[1-(4-azidobenzamidomethyl)ethenyl]-2-carboxy-3- pyrrolidineacetic acid (ABCPA) is described. This novel kainic acid analogue, bearing a photolabile functionality on the isopropenyl side chain, was proven to be a good inhibitor of [3H]CNQX and [3H]kainic acid binding on chick cerebellar membranes. [3H]ABCPA was photoaffinity cross-linked on the membrane fraction of chick cerebellum. Electrophoretic analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed two major radioactive bands with apparent molecular masses of 45 and 33.5 kDa. [3H]ABCPA incorporation in both bands was completely blocked by 2 mM CNQX. When photoaffinity labeling was performed in the presence of 2 mM kainic acid, incorporation of [3H]ABCPA was blocked by approximately 70% in the 45-kDa band and by 18% in the 33.5-kDa band. Incorporation of radioactivity in both bands was blocked by approximately 30% with 10 mM glutamate.

ChemInform Abstract: Efficient Tin Hydride‐Mediated Radical Cyclization of Secondary Amides Leading to Substituted Pyrrolidinones. Part 2. Application to the Synthesis of Aromatic Kainic Acid Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Efficient tin hydride-mediated radical cyclisation of secondary amides leading to substituted pyrrolidinones. Part 2. Application to the synthesis of aromatic kainic acid analogues

An enantioselective synthesis of phenyl allokainoid, starting from D-serine, is reported. Tin-mediated cyclisation of a secondary amide was used in the key step to produce a trisubstituted pyrrolidinone in excellent yield (ca. 80%). The predominant formation of the all-trans diastereoisomer is consistent with a reversible cyclisation to give the thermodynamically more stable product.

An efficient synthesis of 4-aryl kainic acid analogs

A synthesis of 4-aryl kainic acid analogs was achieved using a highly stereoselective Michael addition reaction of dimethyl 2-oxoglutarate with a nitrostyrene. Nitro group reduction, deoxygenation and epimerization complete the synthetic route.

ChemInform Abstract: A Direct Route to Biologically Active Kainic Acid Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Direct Route to Biologically Active Kainic Acid Analogs.

A Direct Route to Biologically Active Kainic Acid Analogs.

ChemInform Abstract: Synthesis of a Simple Kainic Acid Analogue by Means of Carbamoylmethyl Radical Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of a Simple Kainic Acid Analogue by Means of Carbamoylmethyl Radical Cyclization

Synthesis of a Simple Kainic Acid Analogue by Means of Carbamoylmethyl Radical Cyclization

Rapid Assay for the Determination of Two Photoactivatible Kainic Acid Analogues by High-Performance Liquid Chromatography

Abstract An anion-exchange isocratic high-performance liquid chromatographic method for the separation and determination of two kainic acid analogues, namely (2S,3S,4S)-4-[l-(4′-azidobenzoy l)aminomethy lethenyl] -2-carboxy-3-pyrrolidineacetic acid and (2S.3S.4S)-4-[l-(4′-azido-phenyl)thioureylenernethy lethenyl]-2-carboxy-3-pyrro-lidineacetic acid is described. These kainic acid analogues were obtained by coupling dimethyl (2S.3S.4S)-4-(1-aminomethylethenyl)-2-carboxy-1-(9-fluorenylmethoxy-carbonyl)-3-pyrrolidineacetic acid with N-hydroxysuccinimidyl 4-azidobenzoate and 4-azidophenyl isothiocyanate respectively, followed by saponification. The thus obtained products were purified by reversed phase flash column chromatography and separated on Econosphere -NK2, using 5% (v/v) acetonitrile in 50 mM acetate buffer pH 5.5, at a flow rate of 1.5 ml/min. The effect of mobile phase pH, and of the acetonitrile concentration on the resolution between kainic acid and its analogues was also studied. Kainic acid was ...

Glutamic acid-insensitive [ 3H]kainic acid binding in goldfish brain

Kainic acid is supposed to be a specific agonist for a subclass of excitatory glutamate receptors in the vertebrate CNS. An investigation of (2 nM) [ 3H]kainic acid binding sites in goldfish brain, using quantitative autoradiography, has revealed evidence for two types of kainic acid receptors which differ in sensitivity to glutamic acid. l-Glutamic acid (0.1–1 mM) displaced over 95% of specific [ 3H]kainic acid binding elsewhere in the brain but only 10–50% in the cerebellum and cerebellar crest. These structures apparently contain [ 3H]kainic acid binding sites that are extremely insensitive to glutamic acid. The glutamic acid-insensitive [ 3H]kainic acid bindings was not displaced by quisqualic acid kynurenic acid, α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA), or N-methyl- d-aspartatic acid, but was completely displaced by the kainic acid analogue domoic acid. The data indicate that two types of high affinity binding sites for [ 3H]kainic acid exist in the goldfish brain: glutamic acid-sensitive and glutamic acid-insensitive. High affinity [ 3H]kainic acid binding may therefore not always represent binding to subsets of glutamic acid receptors.

ChemInform Abstract: Probing the Topography of Kainate Recognition Sites: Synthesis of a Novel Oxetane‐Containing Kainic Acid Analogue.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Diastereoselective synthesis of ( 2S,3R) 2-carboxy-3-pyrrolidine acetic acid, a simple kainic acid analogue

(25,3R) 2-carboxy-3-pyrrolidine acetic acid was synthetized from (S)-pyroglutamic acid by a route involving the conjugate addition of t-butyl-2- lithiophenylthioacetate to N-methoxycarbonyl α, β-unsaturated lactam.

Probing the topography of kainate recognition sites: Synthesis of a novel oxetane containing kainic acid analogue.

A short synthesis of the conformationally rigidified spirocyclic-kainic acid analogue 2 is described starting from kainic acid. This relatively conservative change in the structure of kainic acid has been found to lead to a loss of affinity for glutamate recognition sites.