Discovery of α-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of ρ1 γ-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone
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Discovery of α-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of ρ1 γ-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone. / Krall, Jacob; Brygger, Benjamin M; Sigurðardóttir, Sara B; Ng, Clarissa K L; Bundgaard, Christoffer; Kehler, Jan; Nielsen, Birgitte; Bek, Toke; Jensen, Anders A; Frølund, Bente.
In: ChemMedChem, Vol. 11, No. 20, 13.09.2016, p. 2299-2310.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Discovery of α-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of ρ1 γ-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone
AU - Krall, Jacob
AU - Brygger, Benjamin M
AU - Sigurðardóttir, Sara B
AU - Ng, Clarissa K L
AU - Bundgaard, Christoffer
AU - Kehler, Jan
AU - Nielsen, Birgitte
AU - Bek, Toke
AU - Jensen, Anders A
AU - Frølund, Bente
N1 - © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2016/9/13
Y1 - 2016/9/13
N2 - The ρ-containing γ-aminobutyric acid type A receptors (GABAA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAA Rs are of interest. In this study, we demonstrate that the partial GABAA R agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood-brain barrier in vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure-activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABAA Rs in a [(3) H]muscimol binding assay and at recombinant human α1 β2 γ2S and ρ1 GABAA Rs using the FLIPR™ membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ1 GABAA R that also displayed significant selectivity for this receptor over the α1 β2 γ2S GABAA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.
AB - The ρ-containing γ-aminobutyric acid type A receptors (GABAA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAA Rs are of interest. In this study, we demonstrate that the partial GABAA R agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood-brain barrier in vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure-activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABAA Rs in a [(3) H]muscimol binding assay and at recombinant human α1 β2 γ2S and ρ1 GABAA Rs using the FLIPR™ membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ1 GABAA R that also displayed significant selectivity for this receptor over the α1 β2 γ2S GABAA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.
U2 - 10.1002/cmdc.201600356
DO - 10.1002/cmdc.201600356
M3 - Journal article
C2 - 27620323
VL - 11
SP - 2299
EP - 2310
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 20
ER -
ID: 165696126