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

• Published in: Journal of medicinal chemistry Vol. 62; no. 12; pp. 5797 - 5809
• Main Authors: Giraudo, Alessandro, Krall, Jacob, Bavo, Francesco, Nielsen, Birgitte, Kongstad, Kenneth T, Rolando, Barbara, De Blasio, Rossella, Gloriam, David E, Löffler, Rebekka, Thiesen, Louise, Harpsøe, Kasper, Frydenvang, Karla, Boschi, Donatella, Wellendorph, Petrine, Lolli, Marco L, Jensen, Anders A, Frølund, Bente
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27-06-2019
• Subjects: GABA Plasma Membrane Transport Proteins - chemistry; GABA Plasma Membrane Transport Proteins - metabolism; gamma-Aminobutyric Acid - chemistry; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacology; Heterocyclic Compounds - chemistry; Humans; Molecular Docking Simulation; Nitrogen - chemistry; Protein Conformation; Receptors, GABA-A - chemistry; Receptors, GABA-A - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00026

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.