Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists

TY - JOUR

T1 - Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists

AU - Petersen, Jette Gellert

AU - Sørensen, Troels Ersted

AU - Damgaard, Maria

AU - Nielsen, Birgitte

AU - Jensen, Anders A.

AU - Balle, Thomas

AU - Bergmann, Rikke

AU - Frølund, Bente

PY - 2014/9/12

Y1 - 2014/9/12

N2 - A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA A receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABAAR binding affinities to native GABAA receptors (Ki 1.1-24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K i 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABAA agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β 2γ2 GABAA receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABAAR agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABAAR area.

AB - A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA A receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABAAR binding affinities to native GABAA receptors (Ki 1.1-24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K i 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABAA agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β 2γ2 GABAA receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABAAR agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABAAR area.

U2 - 10.1016/j.ejmech.2014.07.039

DO - 10.1016/j.ejmech.2014.07.039

M3 - Journal article

C2 - 25038482

SN - 0223-5234

VL - 84

SP - 404

EP - 416

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -