title: A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine.
abstract: A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.
authors.affiliation: Department of Bioinformatics, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Harusawa
authors.forename: Lisa
authors.initials: L
authors.lastname: Araki
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Tomonari
authors.initials: T
authors.lastname: Imazu
authors.forename: Seiichiroh
authors.initials: S
authors.lastname: Takashima
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Takushi
authors.initials: T
authors.lastname: Kurihara
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Remko A
authors.initials: RA
authors.lastname: Bakker
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamatodani
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008760:Methylguanidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C476146:2-cyano-1-methyl-3-(5-(1H-imidazol-4(5)-yl)tetrahydrofuran-2-yl)methylguanidine; C418607:HRH4 protein, human; D017442:Histamine Agonists; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D008760:Methylguanidine