Wikberg J E, Uhlén S
Department of Pharmacology, Umeå University, Sweden.
J Neurochem. 1990 Jul;55(1):192-203. doi: 10.1111/j.1471-4159.1990.tb08838.x.
We have demonstrated previously that [3H]idazoxan, besides being able to bind to alpha 2-adrenergic receptors, may also bind to a nonadrenergic idazoxan-receptor site with high affinity. The idazoxan receptor is tightly bound to cellular membranes, and we have now developed a method to solubilize it from the guinea pig cerebral cortex by using the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The CHAPS-solubilized receptor retains its binding properties for drugs: the membrane-bound, as well as the solubilized, idazoxan receptor shows high affinities for a number of imidazolines (cirazoline, idazoxan, tolazoline, naphazoline, tramazoline, clonidine, and oxymetazoline), some imidazoles (medetomidine, detomidine), and guanfacine. By contrast, catecholamines (adrenaline, noradrenaline, isoprenaline, and dopamine) and a number of other neurotransmitters and neuromodulators (serotonin, histamine, glutamic acid, gamma-aminobutyric acid, glycine, and adenosine) show negligible affinities for the idazoxan receptor. Moreover, the idazoxan receptor shows grossly different binding properties for histamine, cimetidine, and imidazole-4-acetic acid compared to what has been described for the nonadrenergic imidazole site labeled by p-[3H]amino-clonidine, indicating that the two receptor sites are distinct. Radioligand binding data further indicate that cirazoline is an idazoxan receptor-selective drug (KD = 1 nM) showing a 50-210-fold selectivity for binding to the idazoxan receptor when compared to alpha 2-adrenergic receptors and an about 500-fold selectivity when compared to alpha 1-adrenergic receptors. We have also reviewed the literature for possible nonadrenergic actions of idazoxan and cirazoline, and we suggest that idazoxan receptors might be involved in the control of prolactin release from the pituitary.
我们之前已经证明，[3H]咪唑克生除了能够与α2-肾上腺素能受体结合外，还可能以高亲和力与非肾上腺素能咪唑克生受体位点结合。咪唑克生受体与细胞膜紧密结合，我们现在已经开发出一种方法，通过使用去污剂3-[(3-胆酰胺丙基)二甲基铵]-1-丙烷磺酸盐（CHAPS）从豚鼠大脑皮层中溶解该受体。CHAPS溶解的受体保留了其对药物的结合特性：膜结合的以及溶解的咪唑克生受体对多种咪唑啉（西拉唑啉、咪唑克生、妥拉唑啉、萘甲唑啉、曲马唑啉、可乐定和羟甲唑啉）、一些咪唑类（美托咪定、右美托咪定）和胍法辛表现出高亲和力。相比之下，儿茶酚胺（肾上腺素、去甲肾上腺素、异丙肾上腺素和多巴胺）以及许多其他神经递质和神经调节剂（血清素、组胺、谷氨酸、γ-氨基丁酸、甘氨酸和腺苷）对咪唑克生受体的亲和力可忽略不计。此外，与对p-[3H]氨基可乐定标记的非肾上腺素能咪唑位点所描述的情况相比，咪唑克生受体对组胺、西咪替丁和咪唑-4-乙酸表现出截然不同的结合特性，这表明这两个受体位点是不同的。放射性配体结合数据进一步表明，西拉唑啉是一种咪唑克生受体选择性药物（KD = 1 nM），与α2-肾上腺素能受体相比，其与咪唑克生受体结合的选择性为50 - 210倍，与α1-肾上腺素能受体相比，选择性约为500倍。我们还查阅了有关咪唑克生和西拉唑啉可能的非肾上腺素能作用的文献，并认为咪唑克生受体可能参与垂体催乳素释放的控制。
