TY - JOUR

T1 - Five-membered N-heterocyclic Scaffolds as Novel Amino Bioisosteres at gamma-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

AU - Giraudo, Alessandro

AU - Krall, Jacob

AU - Bavo, Francesco

AU - Nielsen, Birgitte

AU - Kongstad, Kenneth Thermann

AU - Rolando, Barbara

AU - De Blasio, Rosella

AU - Gloriam, David E

AU - Löffler, Rebekka

AU - Thiesen, Louise

AU - Harpsøe, Kasper

AU - Frydenvang, Karla

AU - Boschi, Donatella

AU - Wellendorph, Petrine

AU - Lolli, Marco L

AU - Jensen, Anders A.

AU - Frølund, Bente

PY - 2019/6/27

Y1 - 2019/6/27

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.9b00026

DO - 10.1021/acs.jmedchem.9b00026

M3 - Journal article

C2 - 31117514

VL - 62

SP - 5797

EP - 5809

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 12

ER -