Five-Membered N-Heterocyclic Scaffolds as Novel Amino Bioisosteres at γ-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

Abstract

Given the heterogeneity within the γ-aminobutyric acid (GABA) receptor and transporter families, a detailed insight into the pharmacology is still relatively sparse. To enable studies of the physiological roles governed by specific receptor and transporter subtypes, a series of GABA analogues comprising five-membered nitrogen- and sulfur-containing heterocycles as amine bioisosteres were synthesized and pharmacologically characterized at native and selected recombinant GABAA receptors and GABA transporters. The dihydrothiazole and imidazoline analogues, 5–7, displayed moderate GAT activities and GABAA receptor binding affinities in the mid-nanomolar range (K i, 90–450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABAA-αβγ receptors but somewhat lower potency as partial agonists at the GABAA-ρ1 receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABAA-αβγ receptors but not the GABAA-ρ1 receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.

Structure–Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based γ-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect

“…Both at the β 2 /α 1 and at the β 3 /α 1 interfaces (PDB codes 6D6T and 6HUO, respectively) , the ammonium group of GABA (or its bioisosters) establishes an electrostatic interaction with β-Glu155 as well as π–π interactions with the aromatic box formed by β-Y 205 and β-Y 200, while the carboxylate (or its bioisosters) forms electrostatic interactions with α 1 -Arg 67 (Figure S2A). − Due to the high degree of similarity among subunits within the orthosteric binding pocket, the corresponding residues at the other subunits are conserved (β 1 compared to β 2 and β 3 and α 2, α 3, α 4, α 5, and α 6 compared to α 1 ). , Although all the hereby reported compounds do not have any carboxylic function and therefore miss an interaction believed to be essential for high affinity GABA A R binding, some of them reach nM affinities, meaning that one or more of the other chemical features compensate for the lack of the carboxylic group.…”

Isoliquiritigenin Alleviates Semen Strychni-Induced Neurotoxicity by Restoring the Metabolic Pathway of Neurotransmitters in Rats

“…GABA mediates its effects through the ionotropic GABA A receptors (GABRs), which belong to the Cys-loop superfamily of ligand-gated ion channels. The GABRs are pentameric, membrane-bound proteins surrounding an anion-selective pore ( Giraudo et al, 2019 ). When GABA binds to receptors, it suppresses neuronal activity in the adult brain by opening a transmembrane channel permeable to chloride ( Sigel and Steinmann, 2012 ; Zhu et al, 2018 ; Masiulis et al, 2019 ).…”

Structural and stereochemical determinants for hGAT3 inhibition: development of novel conformationally constrained and substituted analogs of (S)-isoserine.

“…Conformational restriction of a exible ligand into a constrained structure that mimics the bioactive conformation is a common strategy in medicinal chemistry, which often leads to enhanced a nity, potency or selectivity by reducing the entropic penalty upon a binding event [18,19]. Although inhibition of a transporter by a competitive substrate such as (S)-isoserine is a more complex process than a speci c binding event, several examples of conformationally constrained inhibitors of SLC6 transporters have already been reported [20][21][22]. Based on this idea, we designed four series of locked isoserine analogs and related variations, with de ned stereochemistry in most cases (Fig.…”