title: Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists.
abstract: Immepip, a conformationally constrained analogue of the histamine congener imbutamine, shows high affinity and functional activity on the human H(3) receptor. Using histamine and its homologues as prototypes, other rigid analogues containing either a piperidine or pyrrolidine ring in the side chain were synthesized and tested for their activities at the human H(3) receptor and the closely related H(4) receptor. In the series of piperidine containing analogues, immepip was found to be the most potent H(3) receptor agonist, whereas its propylene analogue 13a was identified as a high-affinity neutral antagonist for the human H(3) receptor. Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor.
authors.affiliation: Leiden/Amsterdam Center of Drug Research (LACDR), Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ruengwit
authors.initials: R
authors.lastname: Kitbunnadaj
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: De Esch
authors.forename: Roeland C
authors.initials: RC
authors.lastname: Vollinga
authors.forename: Remko
authors.initials: R
authors.lastname: Bakker
authors.forename: Martin
authors.initials: M
authors.lastname: Lutz
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Spek
authors.forename: Emile
authors.initials: E
authors.lastname: Cavoy
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Deltent
authors.forename: Wiro M P B
authors.initials: WM
authors.lastname: Menge
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D003124:Colorimetry; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D006632:Histamine / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D010880:Piperidines; D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; C085755:4-(1H-imidazol-4-ylmethyl)piperidine; D006632:Histamine; D000242:Cyclic AMP