New Highly Potent GABA Uptake Inhibitors Selective for GAT‐1 and GAT‐3 Derived from (R)‐ and (S)‐Proline and Homologous Pyrrolidine‐2‐alkanoic Acids.

Abstract

New Highly Potent GABA Uptake Inhibitors Selective for GAT-1 and GAT-3 Derived from (R)-and (S)-Proline and Homologous Pyrrolidine-2-alkanoic Acids.-Enantiomerically pure N-substituted proline and pyrolidinealkanoic acid derivatives are synthesized and evaluated for their affinity at the GABA transport proteins GAT-1 and GAT-3 with a special emphasis on enantioselectivity of binding and subtype specificity. Among the N-substituted derivatives, pyrrolidines (VII) exhibit the highest affinity to the GAT-1 protein, whereas pyrrolidine (IX) displays excellent inhibitory activity at GAT-3 with a high subtype selectivity with regard to GAT-1. -(FUELEP, G. H.; HOESL, C. E.; HOEFNER, G.; WANNER*, K. T.; Eur.

Selective mGAT2 (BGT-1) GABA Uptake Inhibitors: Design, Synthesis, and Pharmacological Characterization

“…12,17 We will here report the continuation of this new strategy that has also been followed by others. 20,21 The unique pharmacological profile of EF1502 prompted a larger study that disclosed some unique properties of this uptake inhibitor. Not only was EF1502 a potent anticonvulsant but it potentiated the anticonvulsant properties of tiagabine in a synergistic manner without potentiating sedative effects of tiagabine.…”

Peer Review #1 of "GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors (v0.1)"

“…9 is further validated by our SAR and docking protocol, where all three classes A, B and C showed interactions between the protonated nitrogen atom and F294 and between the COOH group and G65. The effect of the COOH group, as well as the protonated nitrogen atom, on the inhibitory potency of hGAT1 modulators has been previously demonstrated by various authors (Zhao et al, 2005;Fülep et al, 2006;Kragler et al, 2008;Pizzi et al, 2011). Therefore, three orders of magnitude decrease in inhibitory potency of compound 37 as compared to compound 1 is may be due to absence of COOH group in its chemical scaffold.…”

“…1. Briefly, a dataset of 580 hGAT1 antagonists, along with their respective binding affinities (IC 50 ) ranging from 0.04-8511 µM, was obtained from the literature Schousboe, 2000;Clausen et al, 2005;Clausen et al, 2006;Fülep et al, 2006;Zheng et al, 2006;Alexander et al, 2007;Reith, 2007;Faust et al, 2010;Alexander et al, 2011;Nakada et al, 2013;Quandt et al, 2013;Sitka et al, 2013). Subsequently, duplicates and fragments were removed from the data, followed by the removal of antagonists with a molecular mass less than 150 and IC 50 >100 µM.…”

“…Previously, various antagonists of hGAT1, including nipecotic acid, guvacine, proline, pyrrolidine, azetidine and THPO derivatives (Dalby, 2000;Andersen et al, 2001;Clausen et al, 2005;Fülep et al, 2006;Faust et al, 2010;Hellenbrand et al, 2016;Schmidt et al, 2017;Lutz et al, 2018;Tóth et al, 2018), have been synthesized and pharmacologically tested and optimized using SAR data. Additionally, several ligand-based strategies including 2D QSAR (Jurik et al, 2013), CoMFA (Zheng et al, 2006) and pharmacophore models (Hirayama et al, 2001;Nowaczyk et al, 2018) have been developed to optimize small molecule inhibitors against hGAT1.…”

Design, Synthesis, and Potent Antiepileptic Activity with Latent Nerve Rehabilitation of Novel γ-Aminobutyric Acid Derivatives

“…28) Accordingly, various antiepileptics related to GABA can be developed based on direct interaction with GABA receptor, or enhancement of GABA accumulation mainly by stimulating the activity of glutamic acid decarboxylase, inhibiting GABA transaminase, or inhibiting GABA-transport protein. [29][30][31][32][33][34][35] These observations raise the possibility that "replacement" procedures that increase GABA level of central nervous system (CNS) may be useful in the treatment of such neuropsychiatric disorders. 36) Nevertheless, most of antiepileptic drugs including GABA analogues have proven to be discontented as they have little effect on the prognosis of patients with intractable epilepsy due to the lack of potential capacity to rehabilitate the nerve nidus or prevent seizure from injuring neuronal cells.…”