β‑Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences

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 IC₅₀ 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 <b>4y</b> that displayed an IC₅₀ of 0.8 μM at EAAT1 with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively. Conversely, the <i>m</i>-CF₃-phenyl analogue <b>4r</b> was a potent selective EAAT2-inhibitor (IC₅₀ = 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

β‑Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences

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 IC₅₀ 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 <b>4y</b> that displayed an IC₅₀ of 0.8 μM at EAAT1 with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively. Conversely, the <i>m</i>-CF₃-phenyl analogue <b>4r</b> was a potent selective EAAT2-inhibitor (IC₅₀ = 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

β‑Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences

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 IC₅₀ 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 <b>4y</b> that displayed an IC₅₀ of 0.8 μM at EAAT1 with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively. Conversely, the <i>m</i>-CF₃-phenyl analogue <b>4r</b> was a potent selective EAAT2-inhibitor (IC₅₀ = 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

Additional file 2: of Labour management guidelines for a Tanzanian referral hospital: The participatory development process and birth attendants’ perceptions

The PartoMa guidelines booklet. (PDF 1608 kb

Additional file 3: of Labour management guidelines for a Tanzanian referral hospital: The participatory development process and birth attendants’ perceptions

A systematic literature search: Labour and delivery guidelines for African low-income settings. (PDF 401 kb

Exploring the Orthosteric Binding Site of the γ‑Aminobutyric Acid Type A Receptor Using 4‑(Piperidin-4-yl)-1-hydroxypyrazoles 3- or 5‑Imidazolyl Substituted: Design, Synthesis, and Pharmacological Evaluation

A series of 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP) 3- or 5-imidazolyl substituted analogues have been designed, synthesized, and characterized pharmacologically. All analogues showed binding affinities in the low micro- to low nanomolar range at native rat GABA_A receptors and were found to be antagonists at the human α₁β₂γ_2s receptor. The structure–activity relationship of the compound series demonstrates distinct differences in size and architecture of previously discovered cavities in the vicinity of the 4-PHP scaffold in the orthosteric binding site

Additional file 2: of Stillbirths and quality of care during labour at the low resource referral hospital of Zanzibar: a case-control study

Maternal deaths. Intra-hospital management preceding the three maternal deaths within the study population. (DOCX 39 kb

A New Phenylalanine Derivative Acts as an Antagonist at the AMPA Receptor GluA2 and Introduces Partial Domain Closure: Synthesis, Resolution, Pharmacology, and Crystal Structure

In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (<i>RS</i>)-<b>3h</b>, showed micromolar affinity for GluA1_o and GluA2(<i>R</i>)_o receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (<i>RS</i>)-<b>3h</b> competitively antagonized GluA2(<i>Q</i>)_i receptors. The X-ray structure of the active enantiomer (<i>S</i>)-<b>3h</b> in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (<i>S</i>)-<b>3h</b> were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (<i>S</i>)-<b>3h</b> induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands

Binding Mode of an α‑Amino Acid-Linked Quinoxaline-2,3-dione Analogue at Glutamate Receptor Subtype GluK1

Two α-amino acid-functionalized quinoxalines, <b>1a</b> (CNG-10301) and <b>1b</b> (CNG-10300), of a quinoxaline moiety coupled to an amino acid moiety were designed, synthesized, and characterized pharmacologically. While <b>1a</b> displayed low affinity at native AMPA, KA, and NMDA receptors, and at homomeric GluK1,3 receptors, the affinity for GluK2 was in the midmicromolar range (<i>K</i>_i = 136 μM), <b>1b</b> displayed low to midmicromolar range binding affinity at all the iGluRs (<i>K</i>_i = 9–126 μM). In functional experiments (outside-out patches excised from transfected HEK293T cells), 100 μM <b>1a</b> partially blocked GluK1 (33% peak response), while GluK2 was unaffected (96% peak response). Furthermore, <b>1a</b> was shown not to be an agonist at GluK1 and GluK2 at 100 μM. On the other hand, 100 μM <b>1b</b> fully antagonized GluK1 (8% peak response) but only partially blocked GluK2 (33% peak response). An X-ray structure at 2.3 Å resolution of <b>1b</b> in the GluK1-LBD (ligand-binding domain) disclosed an unexpected binding mode compared to the predictions made during the design phase; the quinoxaline moiety remains to act as an amino acid bioisostere, but the amino acid moiety is oriented into a new area within the GluK1 receptor. The structure of the GluK1-LBD with <b>1b</b> showed a large variation in domain openings of the three molecules from 25° to 49°, demonstrating that the GluK1-LBD is capable of undergoing major domain movements

Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors

A series of racemic aryl-substituted phenylalanines was synthesized and evaluated in vitro at recombinant rat GluA1–3, at GluK1–3, and at native AMPA receptors. The individual enantiomers of two target compounds, (<i>RS</i>)-2-amino-3-(3,4-dichloro-5-(5-hydroxypyridin-3-yl)­phenyl)­propanoic acid <b>37</b> and (<i>RS</i>)-2-amino-3-(3′-hydroxybiphenyl-3-yl)­propanoic acid <b>38</b>, were characterized. (<i>S</i>)-<b>37</b> and (<i>R</i>)-<b>38</b> were identified as the only biologically active isomers, both being antagonists at GluA2 receptors with <i>K</i>_b of 1.80 and 3.90 μM, respectively. To address this difference in enantiopharmacology, not previously seen for amino acid-based AMPA receptor antagonists, X-ray crystal structures of both eutomers in complex with the GluA2 ligand binding domain were solved. The cocrystal structures of (<i>S</i>)-<b>37</b> and (<i>R</i>)-<b>38</b> showed similar interactions of the amino acid parts but unexpected and different orientations and interactions of the biaromatic parts of the ligands inside the binding site, with (<i>R</i>)-<b>38</b> having a binding mode not previously identified for amino acid-based antagonists