Acid 1b Research Articles

The effect of acid concentration and etch time on morphology and tensile bond strength of primary dentin: An in vitro study.

There are conflicting results concerning the ideal time for etching primary dentin and its effect on the bond strength of adhesive restorative materials. To assess in vitro, the effect of varied acid concentration and etch time on the morphological features and tensile bond strength of primary dentin. Forty healthy primary molars were prepared by exposing the dentin of the occlusal surface, creating a smear layer. A 3 mm × 3 mm test indow was demarcated, and specimens were randomly allocated to four groups (n = 10): Group 1A 10% phosphoric acid, 7 s; Group 1B 10% phosphoric acid, 15 s; Group 2A 37% phosphoric acid, 7 s and Group 2B 37% phosphoric acid, 15 s. Surface analysis was done using atomic force microscope and scanning electron microscope. For tensile bond strength evaluation, 24 specimens prepared as mentioned were mounted in acrylic blocks and allocated to four groups according to the prescribed etching protocol. Resin rods were bonded and tested in tension after 24 h (n = 6). Data were analyzed statistically using unpaired t-test. Etching of primary dentin using 37% phosphoric acid for 7 s produced the highest tensile bond strength of 9.51 ± 2.19 MPa. Etching time of 7 s may improve the adhesion of resin restorative materials with primary dentin.

Chemical study of the stem bark of Phyllanthus emblica (Phyllanthaceae)

AbstractFrom the ethyl acetate extract of the stem bark of Phyllanthus emblica, a mixture of triterpene glycosides (1) and six compounds (2‐7) were isolated. The structure of these compounds were established as 3‐O‐α‐L‐arabinopyranosyloleanolic acid (1a), 3‐O‐α‐L‐arabinopyranosylursolic acid (1b), 16‐dehydropregnenolone (2), periplogenin (3), betulin (4), phyllanthol (5), gallic acid (6) and methyl gallate (7) by 1D, 2D NMR spectroscopies, and high resolution ESI‐MS analysis, as well as comparison with those reported in the literature. The compounds (1a), (1b), (2) and (3) were found for the first time from this genus.

Catalytic Oxidation of Primary C-H Bonds in Alkanes with Bioinspired Catalysts.

Catalytic oxidation of primary C-H bonds of alkanes with a series of iron and manganese catalysts is investigated. Products resulting from oxidation of methylenic sites are observed when hexane (S1) is used as model substrate, while corresponding primary C-H bonds remain unreactive. However, by using 2,2,3,3-tetramethylbutane (S2) as model substrate, which only contains primary alkyl C-H bonds, oxidation takes place catalytically using a combination of hydrogen peroxide, a manganese catalyst and acetic acid as co-catalyst, albeit with modest yields (up to 4.4 TON). Complexes bearing tetradentate aminopyridine ligands provide the best yields, while a related pentadentate ligand provides smaller product yields. The chemoselectivity of the reaction is solvent dependent. Carboxylic acid 2b is observed as major product when the reaction takes place in acetonitrile, because of the facile overoxidation of the first formed alcohol product 2a. Instead the corresponding primary alcohol 2a becomes dominant in reactions performed in 2,2,2-trifluoroethanol (TFE). Polarity reversal of the hydroxyl moiety arising from the strong hydrogen bond donor ability of the latter solvent accounts for the unusual product chemoselectivity of the reaction. The significance of the current results in the context of light alkane oxidation is discussed.

Application of Relay C−H Oxidation Logic to Polyhydroxylated Oleanane Triterpenoids

Summary Although clinical applications of abundant feedstock triterpenoids such as oleanolic acid are limited because of poor solubility and bioavailability, synthetic access to higher hydroxylated oleanane terpenoids is challenging. We now report the use of relay C−H oxidation logic to mimic the processes carried out in nature by P450 monooxygenase enzymes. To this end, we used the C-23-OH as natural handle for a hydrogen-atom transfer to access C-6, enabling the first syntheses of highly oxidized natural products uncargenin C and protobassic acid as well as uncovering the anti-leukemic activity of a synthetic intermediate.

Regulation of boron toxicity responses via glutathione-dependent detoxification pathways at biochemical and molecular levels in Arabidopsisthaliana

The fine-tuned regulation of the Halliwell-Asada cycle (ascorbate-glutathione pathway) in Arabidopsis thaliana under boron (B) toxicity was shown in our previous report. In this study, we investigated the expression levels of some members of the glutathione S-transferase (GST) superfamily, such as phi (GSTF2, GSTF6, GSTF7, and GSTF8), tau (GSTU19), and zeta (GSTZ1) classes in Arabidopsis thaliana that were exposed to 1 mM boric acid (1B) and 3 mM boric acid (3B). Additionally, the expression levels of genes for glutathione (GSH) and phytochelatin biosynthesis as well as miR169 and miR156 were evaluated in Arabidopsis thaliana exposed to 1B and 3B. Moreover, changes in the levels of total GST activity; GSH; and total, protein-bound, and nonprotein thiols were spectrophotometrically determined. GSH levels and nonprotein thiol content did not change significantly following both B-toxicity conditions. Expression levels of GSH1 and GSH2 stayed stable under 1B toxicity; however, GSH1 expression increased significantly under 3B conditions in Arabidopsis thaliana. The expression levels of four genes from phi class members of GST were not dramatically changed under B-toxicity conditions. However, the transcript levels of miR169, ATGSTU19, and ATGSTZ1 were significantly increased after 1B and 3B exposure. These GST genes may have a role in the dramatic increase of total GST activity under toxic B. To the best of our knowledge, this is the first report displaying an integrative view of high-B-induced regulation of GSH-dependent enzymatic machinery at different biological organization levels in Arabidopsis thaliana.

A rare oxidation of camphene to acid and aldehyde in the presence of Lacunar Keggin heteropoly salts

In this work, monolacunary Keggin heteropolyacid salts containing sodium as the countercation were synthesized and evaluated as catalysts on the camphene oxidation with hydrogen peroxide. Under reaction conditions (i.e., 333 K, air atmosphere, CH3CN solution), camphene (1) was selectively oxidized by H2O2, generating two rare products; camphene aldehyde (1a) and camphenylic acid (1b), which have attractive olfactive properties. Notably, these uncommon compounds were obtained with the camphene preserving their carbon skeletal. Among the lacunar Keggin heteropolyacid salts, the Na7PW11O39 lacunar salt was the most active and selective toward oxidation products, completely converting the camphene to (1a) and (1b) products. The catalyst load, the oxidant: camphene molar ratio and the reaction temperature allowed to control the (1a)/ (1b) proportion.

Synthesis, Characterization, Antifungal and Antibacterial Activities of Novel Amide Derivatives of 1,3-Dioxolane

L-Tartaric acid which is chiral compound and commercially available, was converted into 1,3-dioxolane. In the synthetic sequence, 1,3-dioxolane was first formed via protection and partial hydrolysis of L-tartaric acid. Treatment with altered substituted aromatic amines, 1,3-dioxolane gave the desired amides i.e. ethyl 2,2-dimethyl-5-(phenylcarbamoyl)-1,3-dioxolane-4-carboxylate 3a,
 2-(4-(ethoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-5-carboxamido)benzoic acid 3b, ethyl
 5-(4-iodophenylcarbamoyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate 3c, ethyl
 5-(2-chlorophenylcarbamoyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate 3d and ethyl
 5-(2,4-dichlorophenylcarbamoyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate 3e. These chiral derivatives were purified through column chromatographic technique and characterized by different spectroscopic techniques i.e IR, 1H NMR, 13C NMR and EIMS. The antimicrobial activities of these compounds were determined at different concentrations against different strains of bacteria and fungi.

Synthesis of a novel brominated vinylic fatty acid with antileishmanial activity that effectively inhibits the Leishmania topoisomerase IB enzyme mediated by halogen bond formation

Abstract Many marine derived fatty acids, mainly from sponges, possess vinylic halogenated moieties (bromine or iodine) but their assessment as antileishmanial candidates remains elusive. In this work, we undertook the first total synthesis of a novel series of 2-allyl-3-halo-2-nonadecenoic acids, which preferentially inhibit the Leishmania DNA topoisomerase IB enzyme (LTopIB) over the human topoisomerase IB enzyme (hTopIB). The synthesis of 2-allyl-3-bromo-2E-nonadecenoic acid (1a) and 2-allyl-3-chloro-2E-nonadecenoic acid (2a) was achieved through a palladium catalyzed haloallylation of 2-nonadecynoic acid (2-NDA) using either allyl bromide or allyl chloride in the presence of PdCl2(PhCN)2 in 57–83 % overall yields. Among the new halogenated synthetic compounds, 1a was the most inhibitory of LTopIB with an EC50 = 7 μM, while the shorter chain analogs 2-allyl-3-bromo-2E-dodecenoic acid (1b) and 2-allyl-3-chloro-2E-dodecenoic acid (2b), synthesized from 2-dodecynoic acid, were not inhibitory of LTopIB (EC50 > 100 μM) resulting in the overall order of inhibition 1a > 2-NDA > 2a > > 1b ≅ 2b. The acids 1a and 2a inhibit LTopIB by a Gimatecan-independent mechanism. The enhanced LTopIB inhibition of 1a was computationally rationalized in terms of a halogen bond between the bromine in 1a and a DNA phosphate (binding energy = − 4.85 kcal/mol). Acid 1a also displayed preferential cytotoxicity towards Leishmania infantum amastigotes (EC50 = 2.5 μM) over L. infantum promastigotes (EC50 > 25 μM).

Synthesis and biological evaluation of paclitaxel and vorinostat co-prodrugs for overcoming drug resistance in cancer therapy in vitro.

Paclitaxel (PTX) is the first-line treatment drug for breast cancer. However, drug resistance after a course of treatment and low selectivity restricted its clinical utility sometimes. In this study, we successfully bound PTX and vorinostat (SAHA) to form co-prodrugs based on the synergistic anticancer effects. The PTX-SAHA co-prodrugs were conjugated by glycine (1a) and succinic acid (1b) respectively and the former has shown better activity in cytotoxicity, cell cycle arrest and western-blot experiments. Therefore, 1a was further prepared to nanomicelles with mPEG2000-PLA1750 as the carrier by using thin film method. PTX-SAHA co-prodrug nanomicelles were spherical with a particle size of 20-100 nm. In vitro drug release test showed 1a nanomicelles had sustained release effect, which could reduce the resistance of PTX. In vitro cytotoxicity was evaluated by SRB assay in HCT-116 cells, MCF-7 cells and drug-resistant MCF-7/ADR cells. The results showed 1a nanomicelles had comparable or even better cytotoxicity than PTX especially in the MCF-7/ADR cells. All the results suggested that PTX-SAHA co-prodrug nanomicelles were promising treatment for PTX resistance cancer.

Navigating around Patented Routes by Preserving Specific Motifs along Computer-Planned Retrosynthetic Pathways

Summary By keeping track of lists of specific bonds one wishes to preserve, a computer program is able to identify the key disconnections used in the patented syntheses and design synthetic routes that circumvent these approaches. Here, we provide examples of computer-designed syntheses relevant to medicinal chemistry, in which the machine avoids “strategic” disconnections common to industrial patents and is forced to use different starting materials. The ability of modern retrosynthetic planners to navigate around patented solutions may have significant implications for the ways in which intellectual property related to multistep syntheses is protected and/or challenged.

Evaluation of triterpenes derivatives in the viability of Leishmania amazonensis and Trichomonas vaginalis

Trichomonas vaginalis and Leishmania spp. are protozoal species responsible for millions of cases of parasitic diseases worldwide. Considering the potential of natural products and the need for more effective and less toxic alternatives to treat trichomoniasis and leishmaniasis, this study aimed to evaluate the effect of two series of triterpenes derivatives with different modifications at C-3 and C-28 positions of the ursolic acid (UA) and betulinic acid (BA) against trophozoites of Trichomonas vaginalis and promastigotes forms of Leishmania (L.) amazonensis. The compounds modified just at C-3 were the most active. The 3β-acetyl betulinic acid (1b) reduced the trophozoites viability of T. vaginalis at 74%, followed by the 3-oxo ursolic acid and 3-oxo betulinic acid (3a and 3b) compounds (55% of reduction). The compound 3β-isobutyl ursolic acid (7a) inhibited the viability of L. amazonensis promastigotes by 55%. Therefore, analyzing the structure-activity relationship and the data of literature, it is possible to suppose that the inclusion of polar groups in the skeletons could improve the antiprotozoal activity. Overall, further studies are necessary to develop triterpenic derivatives with more powerful trichomonicidal and leishmanicidal properties.

12]aneN3-based lipid with naphthalimide moiety for enhanced gene transfection efficiency

Three cationic lipids derived from [12]aneN3 modified with naphthalimide (1a), oleic acid (1b) and octadecylamine (1c) were designed and synthesized. In vitro transfection showed that all these liposomes can deliver plasmid DNA into the tested cell lines. Among these liposomes, 1a gave the best transfection efficiency (TE) in A549 cells, which was higher than that of lipofectamine 2000. More importantly, the TE of 1a was dramatically increased in the presence of 10% serum. These results suggested that 1a might be a promising non-viral gene vector, and also give further insight for developing novel high performance gene delivery agents.

Synthesis and Biological Evaluation of New Multifunctional Oxazolone Scaffolds Incorporating Phenyl Benzoate Moiety

Oxazolone derivative 3a was utilized as a versatile precursor for the construction of new heterocyclic scaffolds containing imidazole, oxazine, triazine, and triazole rings (compounds 20, 21, 23, and 24, respectively). Furthermore, 4‐aminohippuric acid (2b) was used in the synthesis of various new oxazolone derivatives (13–19) by utilizing of its amino group in several transformations followed by heterocyclization of these compounds with aldehyde 1 via classical Erlenmeyer condensation method to give the targeted oxazolones. On evaluation of these compounds as antioxidant and antibacterial agents, compounds 20 and 24 exhibited a good antioxidant activity, while compounds 20, 23, and 24 exhibited a good antibacterial activity against Escherichia coli and Staphylococcus aureus.

Synthesis and Evaluation of a New 18F-Labeled Radiotracer for Studying the GABAB Receptor in the Mouse Brain.

New GABAB agonists, fluoropyridyl ether analogues of baclofen, have been synthesized as potential PET radiotracers. The compound with highest inhibition binding affinity as well as greatest agonist response, ( R)-4-amino-3-(4-chloro-3-((2-fluoropyridin-4-yl)methoxy)phenyl)butanoic acid (1b), was radiolabeled with 18F with good radiochemical yield, high radiochemical purity, and high molar radioactivity. The regional brain distribution of the radiolabeled ( R)-4-amino-3-(4-chloro-3-((2-[18F]fluoropyridin-4-yl)methoxy)phenyl)butanoic acid, [18F]1b, was studied in CD-1 male mice. The study demonstrated that [18F]1b enters the mouse brain (1% ID/g tissue). The accumulation of [18F]1b in the mouse brain was inhibited (35%) by preinjection of GABAB agonist 1a, suggesting that the radiotracer brain uptake is partially mediated by GABAB receptors. The presented data demonstrate a feasibility of imaging of GABAB receptors in rodents and justify further development of GABAB PET tracers with improved specific binding and greater blood-brain barrier permeability.

Antioxidant activity of salts of 2-(5-R-4-amino-1,2,4-triazole-3-ylthio)acetic acid

Antioxidants are chemical structures that prevent the oxidation of other chemicals. They protect key cell components by neutralizing the harmful effect of free radicals which are natural products of cell metabolism.Oxidative stress leads to serious cell damage which results in various human diseases such as Alzheimer's disease, Parkinson's disease, atherosclerosis, cancer, arthritis, neurodegenerative disorders etc. The deficiency of antioxidants in food also leads to oxidative stress, which indicates a lack of antioxidant substances consumed by humans.Therefore, the search of substances that could not only prevent but also increase the resistance of the human body to active forms of oxygen or nitrogen and interfere with the processes of oxidative stress is an important task of medicine and pharmacy.The purpose of this work was to study the antioxidant activity (AOA) of salts of 2-(5-R-4-R-4H-1,2,4-triazole-3-ylthio)acetic acids with non-enzymatic initiation of free radical oxidation and to establish laws concerning chemical structure and biological effects of the studied substances.Materials and methods. Original derivatives of 1,2,4-triazole were used in the series of screening studies. The antioxidant activity of the compounds in vitro was determined according to the methodical recommendations of the State Pharmacological Center MoH Ukraine using the method of non-enzymatic initiation of lipid peroxide oxidation.Results. Dimethylammonium salt of 2-(4-amino-5-(2-bromophenyl)-1,2,4-triazole-3-ylthio)acetic acid (3c) possessed with a high AOA which reduced the content of TBK-AP by 54,95% ( р˂0,001).Derivatives of 4-amino-1,2,4-triazole had the most distinct AOA containing С5 carbon atoms 2-bromophenyl substituent. Thus, methylammonium salt 3b reduced the TBK-AP content by 80,31 (p˂0,001) which exceeds the reference ascorbic acid by 45,05% and the prototype thiotriazoline by 36,64%.Considering the data of experimental studies it was found that the most active substances among the studied substances were the initial 2-(4-amino-5-(2-bromophenyl)-1,2,4-triasole-3-ylthio)acetic acid (1b) which reduced TBK-AP level at 91,95% (p˂0,001) and its magnesium salt (3a) which suppressed the formation of this final product of LPO at 94,13% (p˂0,001).Some regularities of the chemical structure and AOA of the investigated substances were established after analyzing the data of experimental studies.Replacement of the morpholine cation in the morpholine molecule of 2-(4-amino-5-phenyl-1,2,4-triazole-3-ylthio)acetic acid (2d) on piperidine (2c) is accompanied by the appearance of AOA from 18,18% to 74,95%. Replacement of the same piperidine cation on the morpholine cation in the piperidine molecule of 2-(4-amino-5-(2-bromophenyl)-1,2,4-triazole-3-ylthio)acetic acid is accompanied by the expressive appearance of AOA, which is 90,27% (3f).Conclusions 8 compounds among the 12 which were studied were able to suppress the generation of free radicals in varying degrees of severity and possessed a distinct AOA. It was established that the introduction in the molecule of 2-(4-amino-5-phenyl-1,2,4-triazole-3-ylthio)acetic acid by С2 carbon atom of the phenyl nucleus of bromine atom was accompanied by an increase in the AOA of the studied substances.

H-Bonding Assisted Self-Assembly of Anionic and Neutral Ligand on Metal: A Comprehensive Strategy To Mimic Ditopic Ligands in Olefin Polymerization.

Self-assembly of two neutral ligands on a metal to mimic bidentate ligand coordination has been frequently encountered in the recent past, but self-assembly of an anionic ligand on a metal template alongside a neutral ligand remains an elusive target. Such a self-assembly is hampered by additional complexity, wherein a highly negatively charged anion can form intermolecular hydrogen bonding with the supramolecular motif, leaving no scope for self-assembly with neutral ligand. Presented here is the self-association of anionic ligand 3-ureidobenzoic acid (2a) and neutral ligand 1-(3-(diphenylphosphanyl)phenyl)urea (1a) on a metal template to yield metal complex [{COOC6H4NH(CO)NH2}{Ph2PC6H4NH(CO)NH2}PdMeDMSO] (4a). The identity of 4a was established by NMR and mass spectroscopy. Along the same lines, 3-(3-phenylureido)benzoic acid (2b) and 1-(3-(diphenylphosphanyl)phenyl)-3-phenylurea (1b) self-assemble on a metal template to produce palladium complex [{COOC6H4NH(CO)NHPh}{Ph2PC6H4NH(CO)NHPh}PdMePy] (5c). The existence of 5c was confirmed by Job plot, 1-2D NMR spectroscopy, deuterium labeling, IR spectroscopy, UV-vis spectroscopy, model complex synthesis, and DFT calculations. These solution and gas phase investigations authenticated the presence of intramolecular hydrogen bonding between hydrogen's of 1b and carbonyl oxygen of 2b. The generality of the supramolecular approach has been validated by preparing six complexes from four monodentate ligands, and their synthetic utility was demonstrated in ethylene polymerization. Complex 4a was found to be the most active, leading to the production of highly branched polyethylene with a molecular weight of 55700 g/mol and melting temperature of 112 °C.

A New Depigmenting-Antifungal Methylated Grindelane from Grindelia chiloensis.

The new methylated grindelane diterpenoid, 7β-hydroxy-8(17)-dehydrogrindelic acid (1b), together with the known 7α-hydroxy-8(17)-dehydrogrindelic acid (2a), 6-oxogrindelic acid (3a), 4β-hydroxy-6-oxo-19-norgrindelic (4a), 19-hydroxygrindelic acid (5a), 18-hydroxygrindelic acid (6a), 4α-carboxygrindelic acid (7a), 17-hydroxygrindelic acid (8a), 6α-hydroxygrindelic acid (9a), 8,17-bisnor-8-oxagrindelic acid (10a), 7α,8α-epoxygrindelic acid (11a), and strictanonic acid (12a) as methyl esters were obtained from an Argentine collection of Grindelia chiloensis (Cornel.) Cabrera. Their structures and relative configurations were established on the basis of spectroscopic analysis. CHCl3 extract from the aerial parts and their pure compounds were evaluated for their antifungal and depigmenting effects. Methyl ester derivative of 10a (10b) exhibited a remarkable mycelial growth inhibition against Botritis cinerea with an IC50 of 13.5μgml-1 . While the new grindelane 1b exerted a clear color reduction of the yellow-orange pigment developed by Fusarium oxysporum against UV-induced damage.

Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells

The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9-acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4-carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL-15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing.

Novel water soluble palladium(II) complexes featuring tetrazolylacetic acids and their esters

2-R-2H-Tetrazol-5-ylacetic acids (R=iso-Pr, tert-Bu, CH2COOH) (1a–c) react with PdCl2 in 5% (w/w) MeOH in 1M HCl furnishing the palladium(II) water soluble complexes trans-[PdCl2L2] (2a–c). In the presence of EtOH in the reaction mixture, esterification of the tetrazolylacetoxy groups occurs leading to trans-[PdCl2(ethyl 2-R-2H-tetrazol-5-ylacetate)2] (3a–c). In the case of reaction of 2-tert-butyl-tetrazol-5-ylacetic acid 1b with PdCl2 increasing of the proportion of methanol up to 50% (w/w) led to the esterification to give trans-[PdCl2(methyl 2-tert-butyl-tetrazol-5-ylacetate)2] 4b. Complexation of isomeric 5-methyl-1H-tetrazol-1-ylacetic acid 5 with PdCl2 at the same conditions leads to trans-[PdCl2(5-methyl-1H-tetrazol-1-ylacetic acid)2] 6 and trans-[PdCl2(ethyl 2-(5-methyl-1H-tetrazol-1-yl)acetate)2] 7. The complexes obtained were characterized by HRESI+-MS, 1H, 13C{1H} NMR, and IR spectroscopies as well as by X-ray diffraction (for 2a, 3a, 3b, 4b and 6·H2O). According DSC/TG analysis the thermal decomposition of the complexes occurs by the same mechanism similar to that of the free ligands. In all cases it starts with evolution of molecular nitrogen from the tetrazole ligand which is accompanied by an exothermic effect.

Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.