title: [(3) H]UR-DE257: development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist.
abstract: A series of new piperidinomethylphenoxypropylamine-type histamine H2 receptor (H2 R) 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-(3) H2 )propionic amide ([(3) H]UR-DE257) was performed. The radioligand (specific activity: 63 Ci mmol(-1) ) had high affinity for human, rat, and guinea pig H2 R (hH2 R, Sf9 cells: Kd , saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 revealed high H2 R selectivity on membranes of Sf9 cells, expressing the respective hHx R subtype (Ki values: hH1 R: >10000 nM, hH2 R: 28 nM, hH3 R: 3800 nM, hH4 R: >10000 nM). In spite of insurmountable antagonism, probably due to rebinding of [(3) H]UR-DE257 to the H2 R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2 R affinities in competition binding assays.
authors.affiliation: Institut für Pharmazie, Pharmazeutische/Medizinische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg (Germany).
authors.forename: Paul
authors.initials: P
authors.lastname: Baumeister
authors.forename: Daniela
authors.initials: D
authors.lastname: Erdmann
authors.forename: Sabrina
authors.initials: S
authors.lastname: Biselli
authors.forename: Nicole
authors.initials: N
authors.lastname: Kagermeier
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006325:Heart Atria / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010880:Piperidines / Q000737:chemistry; D011422:Propionates / Q000737:chemistry; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011970:Receptors, Histamine H2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014316:Tritium / Q000737:chemistry
chemical_list: D000577:Amides; D003503:Cyclobutanes; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011422:Propionates; D019275:Radiopharmaceuticals; D011970:Receptors, Histamine H2; C000600808:UR-DE257; D014316:Tritium; C052576:BMY 25368; C029658:propionic acid
keywords: binding kinetics; histamine H2 receptors; insurmountable antagonism; radiochemistry; rebinding