Abstract
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. N-6-(3,4-Dioxo-2-{3-3-(piperidin-1-ylmethyl)phenoxy]-propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide (3HUR-DE257, 24b) was selected for radiosynthesis. The radioligand ...
Abstract
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. N-6-(3,4-Dioxo-2-{3-3-(piperidin-1-ylmethyl)phenoxy]-propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide (3HUR-DE257, 24b) was selected for radiosynthesis. The radioligand (specific activity: 63 Ci • mmol-1) had a high affinity for the human, the rat and the guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 (24a) revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: >10000 nM, hH2R: 28 nM, hH3R: 3800 nM, hH4R: >10000 nM). Regardless of insurmountable antagonism, characteristic for this class of compounds depending on the type of functional assay, and of rebinding of 24b 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.
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