Details

Autor(en) / Beteiligte

• Baumeister, Paul
• Erdmann, Daniela
• Biselli, Sabrina
• Kagermeier, Nicole
• Elz, Sigurd
• Bernhardt, Günther
• Buschauer, Armin

Titel

[3H]UR-DE257: Development of a Tritium-Labeled Squaramide-Type Selective Histamine H2 Receptor Antagonist

Ist Teil von

• ChemMedChem, 2015-01, Vol.10 (1), p.83-93

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2015

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• A series of new piperidinomethylphenoxypropylamine‐type histamine H2 receptor (H2R) antagonists with different substituted “urea equivalents” was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N‐[6‐(3,4‐dioxo‐2‐{3‐[3‐(piperidin‐1‐ylmethyl)phenoxy]propylamino}cyclobut‐1‐enylamino)hexyl]‐(2,3‐3H2)propionic amide ([3H]UR‐DE257) was performed. The radioligand (specific activity: 63 Ci mmol−1) had high affinity for human, rat, and guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR‐DE257 revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: >10 000 nM, hH2R: 28 nM, hH3R: 3800 nM, hH4R: >10 000 nM). In spite of insurmountable antagonism, probably due to rebinding of [3H]UR‐DE257 to the H2R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2R affinities in competition binding assays. Potent, selective H2R antagonists are valuable tools for determining H2R affinities in competition binding assays. Histamine and a number of drugs targeting H2R have been used as radioligands, yet these compounds remain ineffective due to nonspecific binding, low affinity, or short windows of activity. The attachment of a [2,3‐3H2]propionyl group by a six‐membered linker to the squaramide of BMY 25368 resulted in a subtype‐selective and potent radioligand (Kd=31 nM, hH2R‐expressing Sf9 insect cell membranes).