[3H]UR‐DE257: Development of a Tritium‐Labeled Squaramide‐Type Selective Histamine H2 Receptor Antagonist |
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| Authors: | Dr Paul Baumeister Dr Daniela Erdmann Sabrina Biselli Nicole Kagermeier Prof Dr Sigurd Elz Dr Günther Bernhardt Prof Dr Armin Buschauer |
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| Affiliation: | Institut für Pharmazie, Pharmazeutische/Medizinische Chemie, Universit?t Regensburg, Universit?tsstr. 31, 93053 Regensburg (Germany) |
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| 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. 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. |
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| Keywords: | binding kinetics histamine H2 receptors insurmountable antagonism radiochemistry rebinding |
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