Five-Membered N-Heterocyclic Scaffolds as Novel Amino Bioisosteres at γ-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters
| Autor: | Bente Frølund, Kenneth T. Kongstad, Barbara Rolando, Petrine Wellendorph, Louise Thiesen, Birgitte Nielsen, David E. Gloriam, Kasper Harpsøe, Anders A. Jensen, Rossella De Blasio, Jacob Krall, Karla Frydenvang, Donatella Boschi, Marco Lucio Lolli, Rebekka Löffler, Francesco Bavo, Alessandro Giraudo |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Agonist
GABA Plasma Membrane Transport Proteins AGONISTS Nitrogen Protein Conformation medicine.drug_class Imidazoline receptor PHARMACOLOGICAL CHARACTERIZATION BINDING ANALOGS GLUTAMATE GLYCINE SELECTIVITY ANTAGONISTS MODULATION SUBTYPES 01 natural sciences Partial agonist Aminobutyric acid Structure-Activity Relationship 03 medical and health sciences Heterocyclic Compounds Drug Discovery medicine Humans Structure–activity relationship Receptor gamma-Aminobutyric Acid 030304 developmental biology 0303 health sciences GABAA receptor Chemistry Stereoisomerism Transporter Receptors GABA-A 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry nervous system Biochemistry Molecular Medicine |
| Popis: | 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 ( Ki, 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. |
| Databáze: | OpenAIRE |
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