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Background Humour has long been considered an important coping tool for patients with cancer, but published quantitative data about its significance are limited. The purpose of our study was to survey patients with cancer undergoing radiotherapy regarding their opinions about the use of humour in their care. Methods An anonymous 35-item questionnaire evaluating the patient experience, including the value of humour, was developed by an interdisciplinary team of health care providers (hcps) working within the Radiation Medicine program. This anonymous, voluntary, paper-based survey for self-completion required approximately 10 minutes to finish and was administered during the fall of 2018 and the spring of 2019. Results For the 199 patients who completed the survey [108 women, 89 men (2 respondents did not specify)], median age was 68 years. That group represents approximately 30%--35% of the patients on treatment during the study period. Almost all respondents (86%) indicated that, during their visits to the cancer centre, it was "somewhat important" or "very important" for health care providers (hcps) to use appropriate humour, and 61% of respondents indicated using humour "frequently" or "always" when dealing with their individual cancers. Most respondents (79%) said that humour decreased anxiety, and 86% indicated that laughing was considered "somewhat important" or "very important." Approximately 4% of respondents even listed "sense of humour" as being the most important quality that they looked for in their interactions with their hcps. Conclusions Cancer patients undergoing radiotherapy clearly view humour as being important for coping and dealing with their disease, and oncology hcps should routinely consider incorporating the use of appropriate humour into the care that they provide. [ABSTRACT FROM AUTHOR]

Twenty-one simplified analogues of the natural product domoic acid were designed, synthesized, and then characterized at homomeric kainic acid (KA) receptors (GluK1-3,5). LBG20304 displays a high affinity for homomeric GluK5 receptors (IC 50 = 432 nM) with a >40-fold selectivity over homomeric GluK1-3 subtypes and ≫100-fold selectivity over native AMPA and N -methyl d-aspartate receptors. Functional studies of LBG20304 on heteromeric GluK2/5 receptors show no agonist or antagonist functional response at 10 μM, while a concentration of 100 μM at neuronal slices (rat) shows low agonist activity. A molecular dynamics simulation of LBG20304 , in a homology model of GluK5, suggests specific interactions with the GluK5 receptor and an occluded ligand binding domain, which is translated to agonist or partial agonist activity. LBG20304 is a new compound for the study of the role and function of the KA receptors with the aim of understanding the involvement of these receptors in health and disease.

The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2-4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1-8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC 50  = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b)., Competing Interests: Declaration of competing interest Lennart Bunch reports financial support was provided by University of Copenhagen. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Metabotropic glutamate (Glu) receptors (mGlu receptors) play a key role in modulating excitatory neurotransmission in the central nervous system (CNS). In this study, we report the structure-based design and pharmacological evaluation of densely functionalized, conformationally restricted glutamate analogue (1 S ,2 S ,3 S )-2-(( S )-amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic acid ( LBG30300 ). LBG30300 was synthesized in a stereocontrolled fashion in nine steps from a commercially available optically active epoxide. Functional characterization of all eight mGlu receptor subtypes showed that LBG30300 is a picomolar agonist at mGlu 2 with excellent selectivity over mGlu 3 and the other six mGlu receptor subtypes. Bioavailability studies on mice (IV administration) confirm CNS exposure, and an in silico study predicts a binding mode of LBG30300 which induces a flipping of Tyr144 to allow for a salt bridge interaction of the acetate group with Arg271. The Tyr144 residue now prevents Arg271 from interacting with Asp146, which is a residue of differentiation between mGlu 2 and mGlu 3 and thus could explain the observed subtype selectivity.

Competing Interests: The authors declare no conflicts of interest.

The GluN2C subunit exists predominantly, but not exclusively in NMDA receptors within the cerebellum. Antagonists such as UBP1700 and positive allosteric modulators including PYD-106 and 3-acylamino-2-aminopropionic acid derivatives such as UA3-10 (( R )-2-amino-3-{[5-(2-bromophenyl)thiophen-2-yl]carboxamido}propionic acid) represent promising tool compounds to investigate the role of GluN2C-containing NMDA receptors in the signal transduction in the brain. However, due to its high polarity the bioavailability and CNS penetration of the amino acid UA3-10 are expected to be rather low. Herein, three ester prodrugs 12a - c of the NMDA receptor glycine site agonist UA3-10 were prepared and pharmacokinetically characterized. The esters 12a - c showed higher lipophilicity (higher log D 7.4 values) than the acid UA3-10 but almost the same binding at human serum albumin. The acid UA3-10 was rather stable upon incubation with mouse liver microsomes and NADPH, but the esters 12a - c were fast hydrolyzed to afford the acid UA3-10. Incubation with pig liver esterase and mouse serum led to rapid hydrolysis of the esters 12a - c . The isopropyl ester 12c showed a promising log D 7.4 value of 3.57 and the highest stability in the presence of pig liver esterase and mouse serum. These results demonstrate that ester prodrugs of UA3-10 can potentially afford improved bioavailability and CNS penetration., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

N -Methyl-d-aspartate (NMDA) receptors play critical roles in central nervous system function and are involved in variety of brain disorders. We previously developed a series of ( R )-3-(5-furanyl)carboxamido-2-aminopropanoic acid glycine site agonists with pronounced variation in activity among NMDA receptor GluN1/2A-D subtypes. Here, a series of ( R )-2-amino-3-triazolpropanoic acid analogues with a novel chemical scaffold is designed and their pharmacological properties are evaluated at NMDA receptor subtypes. We found that the triazole can function as a bioisostere for amide to produce glycine site agonists with variation in activity among NMDA receptor subtypes. Compounds 13g and 13i are full and partial agonists, respectively, at GluN1/2C and GluN1/2D with 3- to 7-fold preference in agonist potency for GluN1/2C-D over GluN1/2A-B subtypes. The agonist binding mode of these triazole analogues and the mechanisms by which the triazole ring can serve as a bioisostere for amide were further explored using molecular dynamics simulations. Thus, the novel ( R )-2-amino-3-triazolpropanoic acid derivatives reveal insights to agonist binding at the GluN1 subunit of NMDA receptors and provide new opportunities for the design of glycine site agonists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Mazis, Yi, Lotti, Layeux, Schultz, Bunch, Hansen and Clausen.)

The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of ( S )-2-hydroxyhistidine ( 2a ) and ( S )-2-mercaptohistidine ( 2b ) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range ( K i = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at ∼30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist ( K b = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC 50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons.

Anilines are key constituents in biologically active compounds and often obtained from transition metal-catalyzed coupling of an aryl halide with an amine. In this work, we report a transition metal-free method for the synthesis of meta-bromo- and meta-trifluoromethylanilines starting from 3-tribromomethylcyclopentanone or 3-(2-bromo-2-chloro-1,1,1-trifluoroethyl)cyclopentanone, respectively. The scope of the transformation is shown by application of primary, secondary and aromatic amines. The reaction proceeds in acceptable to high yields (20-81 %), and allows for the synthesis of anilines with substitution patterns otherwise difficult to access., (© 2022 Wiley-VCH GmbH.)

NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of ( R )-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a - s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A-D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC 50 = 0.074 μM) with an agonist efficacy of 28% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.

Autism spectrum disorder (ASD) affects an estimated 1 in 54 children aged 8 years in the United States (Maenner MJ, Shaw KA, Baio et al., 2020). For many of these children, there are concomitant eating and/or behavioral challenges that can make managing their nutritional health challenging. This commentary responds to a particularly challenging case in which a pediatric patient with ASD presented to the local hospital's emergency department with severe weight loss and malnutrition., (© 2020. Springer Nature B.V.)

Disrotatory - thermally allowed - 2π-electrocyclic ring-opening reactions require high temperatures to proceed. Herein, we report the first anion-accelerated 2π-electrocyclic ring opening of 6,6-dihalobicyclo[3.1.0]hexan-2-ones at low temperature to give the corresponding meta-halophenols in good to high yields (18 examples, 29-92 % yield, average: 65 %). Many of the phenols have unconventional substitution patterns and are reported here for the first time. Furthermore, the strength of the methodology was shown by the total synthesis of the densely functionalized phenolic natural product caramboxin (isolated as the lactam dehydrate). The reaction mechanism underlying the anion-acceleration was investigated in an ab initio study, which concluded that base-mediated proton abstraction anti to the concurrently departing endo-bromine was the initiating step in an overall concerted reaction mechanism leading directly to the meta-halophenol., (© 2021 Wiley-VCH GmbH.)

The year 2020 has yielded twin crises in the United States: a global pandemic and a public reckoning with racism brought about by a series of publicized instances of police violence toward Black men and women. Current data indicate that nationally, Black Americans are three times more likely than White Americans to contract Covid-19 (with further variance by state), a pattern that underscores the more general phenomenon of health disparity among Black and White Americans (Oppel et al. in The New York Times 2020; APM Research Lab Staff in APM Research Lab 2020). Once exposed, Black Americans are twice as likely to die of the virus. Unsurprisingly, Black Americans report higher levels of fear of Covid-19 than their White peers, but they also report higher levels of hesitancy toward a Covid-19 vaccine. This paper explores why this apparent discrepancy exists. It also provides practical recommendations for how government and public health leaders might address vaccine hesitancy in the context of the twin crises of 2020.

Methaqualone (2-methyl-3-( o -tolyl)-quinazolin-4(3 H )-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABA A receptors (GABA A Rs). In a previous structure-activity relationship (SAR) study probing the importance of 2- and 3-substituents in the quinazolin-4(3 H )-one scaffold, several potent GABA A R PAMs were identified, including 2,3-diphenylquinazolin-4(3 H )-one (PPQ) and 3-(2-chlorophenyl)-2-phenylquinazolin-4(3 H )-one (Cl-PPQ). Here, PPQ was applied as lead in a SAR study of 6-, 7-, and 8-substituents in the quinazolin-4(3 H )-one by synthesis and functional characterization of 36 PPQ analogs at various GABA A R subtypes. While none of the new analogs were significantly more potent than PPQ or displayed pronounced subtype selectivity across the GABA A Rs tested, several interesting SAR observations were extracted from the study. In an in silico study, the putative binding modes of MTQ, PPQ, and Cl-PPQ in the transmembrane β 2 (+) /α 1 (-) interface of the α 1 β 2 γ 2S GABA A R were predicted. Several plausible binding modes were identified for the three PAMs, and rationalization of the molecular basis for their different modulatory potencies was attempted.

We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT 2A /mGlu 2 receptor complex, based on the 5-HT 2A antagonist MDL-100,907 and the mGlu 2 ago-PAM JNJ-42491293 . The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT 2A -, mGlu 2 /Gqo5-, 5-HT 2A /mGlu 2 -, and 5-HT 2A /mGlu 2 /Gqo5-expressing HEK293 cells using a Ca 2+ imaging assay and a [ 3 H]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT 2A /mGlu 2 and 5-HT 2A /mGlu 2 /Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT 2A antagonist and mGlu 2 ago-PAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT 2A /mGlu 2 cells and both 5-HT- and Glu-induced responses in 5-HT 2A /mGlu 2 /Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT 2A , 5-HT 2A /mGlu 2 , and 5-HT 2A /mGlu 2 /Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex.

The excitatory amino acid transporters (EAATs) mediate uptake of the major excitatory neurotransmitter l-glutamate (Glu). The essential functions governed by these transporters in regulating the central Glu level make them interesting therapeutic targets in a wide range of neurodegenerative and psychiatric disorders. l-Aspartate (Asp), another EAAT substrate, has served as a privileged scaffold for the development of EAAT inhibitors. In this study, we designed and synthesized the first β-indolyloxy Asp analogs 15a - d with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of 15a - d were characterized at hEAAT1-3 and rEAAT4 in a conventional [ 3 H]-d-Asp uptake assay. Notably, thiophene analog 15b and the para -trifluoromethyl phenyl analog 15d were found to be hEAAT1,2-preferring inhibitors exhibiting IC 50 values in the high nanomolar range (0.21-0.71 μM) at these two transporters versus IC 50 values in the low micromolar range at EAAT3,4 (1.6-8.9 μM). In summary, the results presented herein open up for further structure-activity relationship studies of this new scaffold., Competing Interests: The authors declare no competing financial interest.

Competitive antagonists for ionotropic glutamate receptors (iGluRs) are highly valuable tool compounds for studying health and disease states in the central nervous system. However, only few subtype selective tool compounds are available and the discovery of antagonists with novel iGluR subtype selectivity profiles remains a profound challenge. In this paper, we report an elaborate structure-activity relationship (SAR) study of the parental scaffold 2,3- trans -3-carboxy-3-phenyl-proline by the synthesis of 40 new analogues. Three synthetic strategies were employed with two new strategies of which one being a highly efficient and fully enantioselective strategy based on C(sp3)-H activation methodology. The SAR study led to the conclusion that selectivity for the NMDA receptors was a general trend when adding substituents in the 5'-position. Selective NMDA receptor antagonists were obtained with high potency (IC 50 values as low as 200 nM) and 3-34-fold preference for GluN1/GluN2A over GluN1/GluN2B-D NMDA receptors.

Discovery of chemical tools for the ionotropic glutamate receptors continues to be a challenging task. Herein we report a diversity-oriented approach to new 2,3- trans -l-proline analogs whereby we study how the spatial orientation of the distal carboxylate group influences the binding affinity and receptor class and subtype selectivity. In total, 10 new analogs were synthesized and 14 stereoisomers characterized in binding assays at native rat ionotropic glutamate receptors, and at cloned human homomeric kainic acid (KA) receptor subtypes GluK1-3. The study identified isoxazole analogs 3d , e , which displayed selectivity in binding at native N -methyl-d-aspartate (NMDA) receptors over native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KA receptors, in the high nanomolar to low micromolar range. Furthermore, analogs 3i-A/B showed a preference in binding affinity for GluK3 over GluK1,2. Finally, analog 3j displayed high nanomolar affinity for native NMDA receptors as well as for homomeric GluK3 receptors.

In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl- N -( o -tolyl)imidazo[1,2- a ]pyridin-3-amine ( 3a ) which showed a >20-fold preference for inhibition of EAAT3 (IC 50 = 13 μM) over EAAT1,2,4 (EAAT1: IC 50 ∼ 250 μM; EAAT2,4: IC 50 > 250 μM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the o -tolyl group (compound 5b ) and the chemical nature of the substituent in the 2-position (compound 7b ) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC 50 = 7.2 μM) over EAAT1,2,4 (IC 50 ∼ 250 μM).

Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2 S,3 R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 K i ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor ( K i = 0.61 μM) over GluN1/GluN2B-D ( K i = 2.7-62 μM).

Aspartate (Asp) derivatives are privileged compounds for investigating the roles governed by excitatory amino acid transporters (EAATs) in glutamatergic neurotransmission. Here, we report the synthesis of various Asp derivatives with (cyclo)alkyloxy and (hetero)aryloxy substituents at C-3. Their pharmacological properties were characterized at the EAAT1-4 subtypes. The l- threo-3-substituted Asp derivatives 13a-e and 13g-k were nonsubstrate inhibitors, exhibiting pan activity at EAAT1-4 with IC 50 values ranging from 0.49 to 15 μM. Comparisons between (dl- threo)-19a-c and (dl- erythro)-19a-c Asp analogues confirmed that the threo configuration is crucial for the EAAT1-4 inhibitory activities. Analogues (3b-e) of l-TFB-TBOA (3a) were shown to be potent EAAT1-4 inhibitors, with IC 50 values ranging from 5 to 530 nM. Hybridization of the nonselective EAAT inhibitor l-TBOA with EAAT2-selective inhibitor WAY-213613 or EAAT3-preferring inhibitor NBI-59159 yielded compounds 8 and 9, respectively, which were nonselective EAAT inhibitors displaying considerably lower IC 50 values at EAAT1-4 (11-140 nM) than those displayed by the respective parent molecules.

The retigabine analog 2-amino-4-[(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504) is a positive allosteric modulator (PAM) of γ-aminobutyric acid A receptors (GABA A Rs), and the modulator has been used in ex vivo/in vivo studies to probe the physiological roles of native δ-containing GABA A Rs. In this study, the functional properties and mode of action of AA29504 were investigated at human GABA A Rs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology. AA29504 was found to be an allosteric GABA A R agonist displaying low intrinsic activities at 3-30 μM. AA29504 was essentially equipotent as a PAM at the 13 GABA A R subtypes tested (EC 50 : 0.45-5.2 μM), however GABA EC 5 -evoked currents through αβδ subtypes were modulated to substantially higher levels than those through αβγ 2S subtypes (relative to GABA I max ). While the δ/γ 2S -difference clearly was key for this differential GABA efficacy modulation, studies of the AA29504-mediated modulation of different α 4,5,6 -containing αβ, αβγ 2S and αβδ GABA A Rs revealed the α-subunit identity to be another important determinant. Based on its functional properties at numerous mutant GABA A Rs and on in silico analysis of its low-energy conformations, AA29504 is proposed to act through an allosteric site in the transmembrane β (+) /α (-) interface in the GABA A R also targeted by etomidate and several other modulators. In contrast to these modulators, however, AA29504 did not display substantial β 2 /β 3 -over-β 1 GABA A R preference, which challenges the notion of ligands targeting this site always possessing this subtype-selectivity profile. Hence, the detailed pharmacological profiling of AA29504 both highlights the complexity of allosteric GABA A R modulation and provides valuable information about this modulator as a pharmacological tool., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire such when treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by a structure-activity study of the broad-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and thereby an increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathways by NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells.

More than two decades ago, the quinoxalinedione scaffold was shown to act as an α-amino acid bioisoster. Following extensive structure-activity relationship (SAR) studies, the antagonists DNQX, CNQX, and NBQX in the ionotropic glutamate receptor field were identified. In this work, we revisit the quinoxalinedione scaffold and explore the incorporation of an acid functionality in the 6-position. The SAR studies disclose that by this strategy it was possible to tune in iGluR selectivity among the AMPA, NMDA, and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogues are compound 2m being a high affinity ligand for native AMPA receptors (IC 50 = 0.48 μM), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and compounds 2s,t,u are selective ligand for the GluK1 receptor. Most interestingly, compound 2w was shown to be a GluK3-preferring ligand with full selectivity over native AMPA, KA and NMDA receptors.

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 (K i = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC 50 = 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.

In this study inspired by previous work on 3-substituted Asp analogues, we designed and synthesized a total of 32 β-sulfonamide Asp analogues and characterized their pharmacological properties at the excitatory amino acid transporter subtypes EAAT1, EAAT2, and EAAT3. In addition to several potent EAAT inhibitors displaying IC 50 values ∼1 μM at all three subtypes, this elaborate structure-activity relationship also identified analogues exhibiting distinct preferences or selectivities for specific transporter subtypes. Introduction of two fluorine atoms on the phenyl ring yielded analogue 4y that displayed an IC 50 of 0.8 μM at EAAT1 with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively. Conversely, the m-CF 3 -phenyl analogue 4r was a potent selective EAAT2-inhibitor (IC 50 = 2.8 μM) exhibiting 30- and 50-fold selectivity over EAAT1 and EAAT3, respectively. In conclusion, even small structural differences in these β-sulfonamide Asp analogues provide analogues with diverse EAAT subtype selectivity profiles.

Screening of a small compound library at the three excitatory amino acid transporter subtypes 1-3 (EAAT1-3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC 50 20 μM) compared to EAAT2 and EAAT3 (IC 50 > 300 μM). This prompted us to subject 1a to an elaborate structure-activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters.

In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1'-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood-brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg(-1) ) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg(-1) ) did not induce acute effects or any visible changes in behavior., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6-8). In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, 2a-d. Most interestingly, 2a retained a selective agonist activity profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III, subtypes mGlu4,6,8. In general, 2d was 20-fold more potent than 2c and potently activated mGlu4,6,8 in the low-mid nanomolar range.