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

Jacob Krall; Benjamin M Brygger; Sara B Sigurðardóttir; Clarissa K L Ng; Christoffer Bundgaard; Jan Kehler; Birgitte Nielsen; Toke Bek; Anders A Jensen; Bente Frølund

doi:10.1002/cmdc.201600356

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

Jacob Krall, Benjamin M Brygger, Sara B Sigurðardóttir, Clarissa K L Ng, Christoffer Bundgaard, Jan Kehler, Birgitte Nielsen, Toke Bek, Anders A Jensen, Bente Frølund

3 Citations (Scopus)

Abstract

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.

Original language	English
Journal	ChemMedChem
Volume	11
Issue number	20
Pages (from-to)	2299-2310
Number of pages	12
ISSN	1860-7179
DOIs	https://doi.org/10.1002/cmdc.201600356
Publication status	Published - 19 Oct 2016

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Krall, J., Brygger, B. M., Sigurðardóttir, S. B., Ng, C. K. L., Bundgaard, C., Kehler, J., Nielsen, B., Bek, T., Jensen, A. A., & Frølund, B. (2016). 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. ChemMedChem, 11(20), 2299-2310. https://doi.org/10.1002/cmdc.201600356

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 et al.

In: ChemMedChem, Vol. 11, No. 20, 19.10.2016, p. 2299-2310.

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

Krall, J, Brygger, BM, Sigurðardóttir, SB, Ng, CKL, Bundgaard, C, Kehler, J, Nielsen, B, Bek, T, Jensen, AA & Frølund, B 2016, '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', ChemMedChem, vol. 11, no. 20, pp. 2299-2310. https://doi.org/10.1002/cmdc.201600356

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abstract = "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{\texttrademark} 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.",

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AU - Sigurðardóttir, Sara B

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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

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