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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists. / Petersen, Jette Gellert; Sørensen, Troels Ersted; Damgaard, Maria; Nielsen, Birgitte; Jensen, Anders A.; Balle, Thomas; Bergmann, Rikke; Frølund, Bente.

In: European Journal of Medicinal Chemistry, Vol. 84, 2014, p. 404-416.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Petersen, JG, Sørensen, TE, Damgaard, M, Nielsen, B, Jensen, AA, Balle, T, Bergmann, R & Frølund, B 2014, 'Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists', European Journal of Medicinal Chemistry, vol. 84, pp. 404-416. https://doi.org/10.1016/j.ejmech.2014.07.039

APA

Petersen, J. G., Sørensen, T. E., Damgaard, M., Nielsen, B., Jensen, A. A., Balle, T., Bergmann, R., & Frølund, B. (2014). Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists. European Journal of Medicinal Chemistry, 84, 404-416. https://doi.org/10.1016/j.ejmech.2014.07.039

Vancouver

Petersen JG, Sørensen TE, Damgaard M, Nielsen B, Jensen AA, Balle T et al. Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists. European Journal of Medicinal Chemistry. 2014;84:404-416. https://doi.org/10.1016/j.ejmech.2014.07.039

Author

Petersen, Jette Gellert ; Sørensen, Troels Ersted ; Damgaard, Maria ; Nielsen, Birgitte ; Jensen, Anders A. ; Balle, Thomas ; Bergmann, Rikke ; Frølund, Bente. / Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 84. pp. 404-416.

Bibtex

@article{c3cdeb253b2e481dad6c90cca87aa8d9,
title = "Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel γ-aminobutyric acidA receptor agonists",
abstract = "A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABAA 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 (Ki 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 α1β2γ2 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.",
author = "Petersen, {Jette Gellert} and S{\o}rensen, {Troels Ersted} and Maria Damgaard and Birgitte Nielsen and Jensen, {Anders A.} and Thomas Balle and Rikke Bergmann and Bente Fr{\o}lund",
year = "2014",
doi = "10.1016/j.ejmech.2014.07.039",
language = "English",
volume = "84",
pages = "404--416",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson",

}

RIS

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

Y1 - 2014

N2 - A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABAA 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 (Ki 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 α1β2γ2 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 GABAA 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 (Ki 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 α1β2γ2 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

VL - 84

SP - 404

EP - 416

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -

ID: 118590454