[H-3]UR-DE257: Development of a Tritium-Labeled Squaramide-Type Selective Histamine H-2 Receptor Antagonist

作者：Baumeister Paul; Erdmann Daniela; Biselli Sabrina; Kagermeier Nicole; Elz Sigurd; Bernhardt Guenther; Buschauer Armin^*

来源：ChemMedChem, 2015, 10(1): 83-93.

DOI：10.1002/cmdc.201402344

• binding kinetics
• histamine H-2 receptors
• insurmountable antagonism
• radiochemistry
• rebinding

A series of new piperidinomethylphenoxypropylamine-type histamine H-2 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-H-3(2))propionic amide ([H-3]UR-DE257) was performed. The radioligand (specific activity: 63Cimmol(-1)) had high affinity for human, rat, and guinea pig H2R (hH(2)R, Sf9 cells: K-d, saturation binding: 31nM, kinetic studies: 20nM). UR-DE257 revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hH(x)R subtype (K-i values: hH(1)R: >10000nM, hH(2)R: 28nM, hH(3)R: 3800nM, hH(4)R: >10000nM). In spite of insurmountable antagonism, probably due to rebinding of [H-3]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.

• 出版日期2015-1