Kojic Acid Derivatives as Histamine H3 Receptor Ligands

Abstract

The histamine H 3 receptor (H 3 R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H 3 R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H 3 R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of g-pyranones with respect to the different moieties of the H 3 R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H 3 R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H 3 R ligands with a modified profile of action.

Anticonvulsant effects of isomeric nonimidazole histamine H₃ receptor antagonists

“…After purification (as described for compound P3 ), the resulting light solid was crystallized as hydrochloride from 2-propanol (1.5 g, 50%; Scheme 1). 31,36,37 Chemical formula: C 15 H 23 NO 2 × HCl. 1 H NMR (DMSO- d 6 ): δ 10.74 (br s, 1H, NH), 7.23 (d, J =8.6, 2H, ph-2,5 H ), 6.90 (d, J =8.6, 2H, ph-3,5 H ), 4.43 (s, 2H, C H 2 –OH), 4.04 (t, J =6.0, 2H, prop-1 H 2 ), 3.43 (m, 2H, pip-2,6 H eq ), 3.16–3.13 (m, 2H, prop-3 H 2 ), 2.92–2.76 (m, 2H, pip-2,6 H ax ), 2.23–2.19 (m, 2H, prop-2 H 2 ), 1.85–1.78 (m, 5H, pip-3,5 H 2 , pip-4 H eq ), 1.45–1.34 (m, 1H, pip-4 H ax ).…”

“…As described in previous publications,31,37–41 the antagonist affinity for human histamine H 3 Rs was tested utilizing radioligand binding assays and HEK-293 cell membrane preparations. The competition binding experiments were conducted on membranes (20–25 µg/well in a final volume of 0.2 mL binding buffer), which were incubated with [ 3 H] N α -MeHA (2 nM; 85 Ci/mmol) and a variety of concentrations range of the respective test ligand.…”

“…As described previously, binding assays conducted on CHO-K1 cells stably expressing the hH 1 R were used to determine the antagonist affinity of the respective test compound for hH 1 Rs 31,37–41. The experimental assays were conducted in triplicates with at least four appropriate concentrations in the range of 100 nM–100 µM of the respective test compound.…”

“…As described previously, binding assay experiments were conducted to determine the antagonist affinity of the respective test compound to hH 4 Rs 31,37–41. Briefly, the competition binding experiments were run on incubating membranes, 35 µg/well (prepared from Sf9 cells expressing hH 4 R, coexpressed with G protein G γi2 and Gβ 1γ2 subunits) in a final volume of 0.2 mL containing binding buffer and [ 3 H] histamine (10 nM, 15.3 Ci/mmol) in a 96-well microtiterplate.…”

Bodilisant—A Novel Fluorescent, Highly Affine Histamine H3 Receptor Ligand

“…28 The intermediate II was used for alkylation of methyl 4-hydroxybenzoate by Williamson ether reaction. 29 Methyl ether III 28 was cleaved in basic milieu.…”