一种选择性人H(4)受体激动剂：(-)-2-氰基-1-甲基-3-[(2R,5R)-5-[1H-咪唑-4(5)-基]四氢呋喃-2-基]甲基胍。

A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine.

作者信息

Hashimoto Takeshi, Harusawa Shinya, Araki Lisa, Zuiderveld Obbe P, Smit Martine J, Imazu Tomonari, Takashima Seiichiroh, Yamamoto Yumiko, Sakamoto Yasuhiko, Kurihara Takushi, Leurs Rob, Bakker Remko A, Yamatodani Atsushi

机构信息

Department of Bioinformatics, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan.

出版信息

J Med Chem. 2003 Jul 3;46(14):3162-5. doi: 10.1021/jm0300025.

DOI:10.1021/jm0300025

PMID:12825954

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.

摘要

设计、合成了一系列与手性4(5)-(5-氨甲基四氢呋喃-2-基)咪唑(1)相关的16种化合物，并通过放射性配体置换研究和功能测定对SK-N-MC细胞中表达的人H(3)和H(4)受体进行了体外研究。其中，氨基化合物的(2S,5S)-异构体1d在H(3)受体上的选择性比H(4)受体高约300倍。另一方面，(2R,5S)-和(2R,5R)-氰基胍3b和3c，其中化合物1b和1c的氨基被氰基胍部分取代，分别以6.65和7.11的pEC(50)值与H(4)受体结合，对H(3)受体的选择性大于40倍。因此，3b和3c是首批选择性H(4)受体激动剂。