title: Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor.
abstract: The histamine H3 receptor (H3R) has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine) and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine) at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhong
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Chen
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Fenyan
authors.initials: F
authors.lastname: Yang
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Naiming
authors.initials: N
authors.lastname: Zhou
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D057809:HEK293 Cells; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051381:Rats; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017442:Histamine Agonists; D010880:Piperidines; D018100:Receptors, Histamine H3; C578331:ZEL-H16; D037342:Pertussis Toxin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3