Highly Potent Fluorescence‐Tagged Nonimidazole Histamine H₃ Receptor Ligands

Abstract

Different (3‐phenoxypropyl)piperidine derivatives have been coupled to fluorescent moieties (5‐dimethylaminonaphthalene‐1‐sulfonyl, carbazol‐9‐ylcarbonyl, 2‐cyanoisoindol‐1‐yl, 2‐cyanobenzo[f]isoindol‐1‐yl, 2,4‐dinitrobenzen‐1‐yl, 2,4‐diaminophenyl, 7‐nitrobenzofurazan‐4‐yl, 7‐aminosulfonylbenzofurazan‐4‐yl, 4‐methylcoumarin‐6‐yl) as novel histamine H3 receptor ligands. They have been synthesised starting from piperidine in a few steps. The compounds display good to excellent histamine hH3 receptor affinities with Ki values ranging from 13.4 to 0.048 nM. Some of the new compounds belong to the most potent ligands known so far and may act as tools for identification and understanding of the binding site on the histamine H3 receptor. In vivo screening on selected derivatives of Sanger’s reagent showed antagonist potencies with ED50 values from 7.9 to 0.39 mg kg−1, p.o.

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

“…3-(Piperidin-1-yl)propan-1-ol Hydrochloride (P1) 9,19,20) Piperidine (51.1 g, 0.6 mol), 3-chloropropan-1-ol (47.3 g, 0.5 mol), potassium carbonate (74.3 g, 0.75 mol) and potassium iodide (8.3 g, 0.05 mol) were refluxed in absolute acetone (300 ml) during 72 h. The mixture was allowed to cool to room temperature, inorganic components were removed by filtration and the filtrate was concentrated to dryness. Purification of the crude oil was achieved by means of distillation (20 mbar, 95°C).…”

“…Purification of the crude oil was achieved by means of distillation (20 mbar, 95°C). The oily product was crystallized as hydrochloride from 2-propanol (white solid, 54.6 g, 79% 1-(3-Chloropropyl)piperidine Hydrochloride (P2) 9,19,20) Alcohol P1 (13.4 g, 0.08 mol) was suspended in toluene (100 ml). Under inert atmosphere and at 0°C an excess of thionyl chloride (11.6 ml, 0.16 mol) was added dropwise.…”

“…The crude product was re-crystallized from ethanol (beige solid, 14.8 g, quantitative conversion). Methyl 4-(3-(Piperidin-1-yl)propoxy)benzoate (P3) 9,20) Chloride P2 (3.0 g, 15.1 mmol), methyl 4-hydroxybenzoate (2.6 g, 16.8 mmol), potassium carbonate (9.0 g, 90.6 mmol) and potassium iodide (2.5 g, 15.1 mmol) were refluxed in absolute acetone (100 ml) during 3 d. The crude was taken up in soda lye (2 N) and purified as described for compound P3. The resulting product was a brown oil (2.6 g, 61% …”

“…9,19,20) Briefly, piperidine was alkylated with 3-chloropropan-1-ol under basic conditions (Chart 1). The resulting alcohol precursor P1 was chlorinated (P2) and subsequently transferred to phenol ether synthesis.…”

“…Reaching the isoelectric point of the product (close to neutral pH value) it crystallized as a white solid (1.9 g, quantitative conversion). 9,20) Chloride P2 (3.0 g, 15.1 mmol), 4-hydroxybenzonitrile (2.0 g, 16.8 mmol), potassium carbonate (9.0 g, 90.6 mmol) and potassium iodide (2.5 g, 15.1 mmol) were refluxed in absolute acetone (100 ml) during 3 d. After cooling the inorganic salts were filtered off and the filtrate was concentrated under reduced pressure. The remaining residue was taken up in soda lye (5 N) and extracted with methylene chloride.…”