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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).