Yanai K, Ryu J H, Sakai N, Takahashi T, Iwata R, Ido T, Murakami K, Watanabe T
Department of Pharmacology I, Tohoku University School of Medicine, Sendai, Japan.
Jpn J Pharmacol. 1994 Jun;65(2):107-12. doi: 10.1254/jjp.65.107.
The release and synthesis of neuronal histamine are regulated by histaminergic autoreceptors named as histamine H3 receptors. The development of radiolabeled histamine H3 antagonists is needed to characterize the binding of antagonists to these receptors. Here we describe the binding characteristics of a new histamine H3-receptor antagonist, [3H]S-methylthioperamide (SMT), to rat tissues, and compare its binding with that of 3Halpha-methylhistamine ((R)alpha MH), a selective histamine H3-receptor agonist. The binding of [3H]SMT to the membranes of rat forebrain was found to be stereoselective, saturable, reversible and temperature-dependent. Saturation binding experiments indicated a single class of high affinity sites for [3H]SMT in forebrain membranes (KD = 2.1 nM, Bmax = 24.3 pmol/g of tissue at 4 degrees C). The Bmax was approximately 3 times that of 3Halpha MH binding to rat forebrain membranes (KD = 2.5 nM, Bmax = 7.3 pmol/g of tissue at 25 degrees C). Autoradiographic images of [3H]SMT binding in the brain were essentially the same as those of 3Halpha MH. [3H]SMT also bound appreciably to peripheral tissues (the liver, adrenal, stomach, ileum, kidney, lung and bladder), whereas the 3Halpha MH bindings to these peripheral tissues were negligible. These results indicate that [3H]SMT binds to H3 receptors primarily in the central nervous system, and that it also has high affinity toward non-H3 receptors, probably hemoproteins, in peripheral tissues.
神经元组胺的释放和合成受名为组胺H3受体的组胺能自身受体调控。需要开发放射性标记的组胺H3拮抗剂来表征拮抗剂与这些受体的结合情况。在此，我们描述了一种新型组胺H3受体拮抗剂[3H]S-甲基硫代哌酰胺（SMT）与大鼠组织的结合特性，并将其与选择性组胺H3受体激动剂3Hα-甲基组胺（(R)α MH）的结合情况进行比较。发现[3H]SMT与大鼠前脑细胞膜的结合具有立体选择性、饱和性、可逆性且依赖温度。饱和结合实验表明，前脑细胞膜中存在一类单一的[3H]SMT高亲和力位点（4℃时KD = 2.1 nM，Bmax = 24.3 pmol/g组织）。Bmax约为3Hα MH与大鼠前脑细胞膜结合（25℃时KD = 2.5 nM，Bmax = 7.3 pmol/g组织）的3倍。[3H]SMT在脑中的放射自显影图像与3Hα MH的基本相同。[3H]SMT也能与外周组织（肝脏、肾上腺、胃、回肠、肾脏、肺和膀胱）显著结合，而3Hα MH与这些外周组织的结合可忽略不计。这些结果表明，[3H]SMT主要与中枢神经系统中的H3受体结合，并且它对外周组织中的非H3受体（可能是血红蛋白）也具有高亲和力。
