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Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at -Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

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Alessandro Giraudo, Jacob Krall, Francesco Bavo, Birgitte Nielsen, Kenneth Thermann Kongstad, Barbara Rolando, Rosella De Blasio, David E Gloriam, Rebekka Löffler, Louise Thiesen, Kasper Harpsøe, Karla Frydenvang, Donatella Boschi, Petrine Wellendorph, Marco L Lolli, Anders A. Jensen, Bente Frølund

Given the heterogeneity within the GABA receptor and transporter families, the 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 analogs 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 analogs, 5-7, displayed moderate GAT activities and GABAA receptor binding affinities in the mid- to high-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. The methylated analogs 8-10 displayed negligible GAT activity and reduced agonist activity on all GABAA-αβγ subtypes, whereas cis-8, 9, and u-10 were found to be weak GABA-ρ antagonists, which could be rationalized by the receptor models. This study illustrates how subtle structural differences in these novel amino GABA bioisosteres can result in diverse pharmacological profiles in terms of selectivity and efficacy.

Original languageEnglish
JournalJournal of Medicinal Chemistry
ISSN0022-2623
DOIs
Publication statusE-pub ahead of print - 22 May 2019

ID: 218522507