title: Synthesis and pharmacological characterization of novel fluorescent histamine H2-receptor ligands derived from aminopotentidine.
abstract: In an effort to develop a non-radioactive alternative to the [3H]tiotidine and [125I]iodoaminopotentidine binding assays for the histamine H2-receptor (H2R), primary amines related to aminopotentidine were prepared and coupled with the succinimidyl esters of the bulky fluorescent dyes S0536 and BODIPY 650/665-X. The primary amines exhibited different degrees of antagonistic potency at the human and guinea pig H2R. Surprisingly, one compound (5) coupled to the cyanine dye S0536 acted as potent partial agonist/antagonist at the H2R (KB approximately 50 nM; EC50 approximately 100-150 nM). Compounds coupled to the BODIPY dye exhibited moderately high H2R-affinity, too. Thus, the H2R accommodates bulky fluorophores, probably through interaction with extracellular receptor domains. The compounds presented herein provide a starting point for the optimization of fluorescent H2R ligands with respect to affinity and fluorescence as valuable tools to analyze the molecular mechanisms of H2R activation.
authors.affiliation: High Throughput Screening Laboratory, The University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Sheng-Xue
authors.initials: SX
authors.lastname: Xie
authors.forename: Georgiana
authors.initials: G
authors.lastname: Petrache
authors.forename: Erich
authors.initials: E
authors.lastname: Schneider
authors.forename: Qi-Zhuang
authors.initials: QZ
authors.lastname: Ye
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011970:Receptors, Histamine H2 / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D006146:Guanidines; D008024:Ligands; D010880:Piperidines; D011970:Receptors, Histamine H2; C103275:aminopotentidine