A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine.
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.
Hashimoto
Takeshi
T
Department of Bioinformatics, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan.
Harusawa
Shinya
S
Araki
Lisa
L
Zuiderveld
Obbe P
OP
Smit
Martine J
MJ
Imazu
Tomonari
T
Takashima
Seiichiroh
S
Yamamoto
Yumiko
Y
Sakamoto
Yasuhiko
Y
Kurihara
Takushi
T
Leurs
Rob
R
Bakker
Remko A
RA
Yamatodani
Atsushi
A
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
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