Watson J M, Hunter A J, Brown A M, Middlemiss D N
Neurosciences Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Eur J Pharmacol. 1999 Apr 1;370(1):69-77. doi: 10.1016/s0014-2999(99)00081-3.
We have investigated the pharmacology of the functionally selective muscarinic M1 receptor partial agonist, sabcomeline [SB-202026 (R-(Z)-(+)-alpha-(methoxyamino)-1-azabicyclo[2.2.2] octane-3-acetonitrile)], in rat cortex and heart using radioligand binding and functional studies. The Quinuclidinyl benzilate/Oxotremorine-M acetate ratio from radioligand binding studies suggested that sabcomeline and xanomeline [3(3-hexyloxy-1,25-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-met hylpyridine] are muscarinic receptor partial agonists in cortical and heart membranes. In [35S]GTPgammaS binding studies in rat cortex, carbachol stimulated binding via muscarinic M2/M4 receptors which could be blocked by sabcomeline with a pA2 of 7.2. In rat heart membranes, carbachol also stimulated [35S]GTPgammaS binding studies through muscarinic M2 receptors. Sabcomeline caused a small stimulation of basal [35S]GTPgammaS binding in both rat and heart tissues. Sabcomeline did not stimulate phosphoinositide hydrolysis in rat cortical slices, but did block the muscarinic M1 receptor-mediated response caused by carbachol with apparent pKb of 6.9. Xanomeline and milameline also had no effect on phosphoinositide hydrolysis up to 100 microM. In adenylyl cyclase studies in rat atria, sabcomeline inhibited forskolin-stimulated adenylyl cyclase activity to a similar extent to that of carbachol, xanomeline and milameline. The present study, using the techniques of radioligand binding, supports previous publications which have claimed that sabcomeline is a muscarinic receptor partial agonist. As expected, this study shows that the functional actions of this compound at muscarinic receptor subtypes and in different tissues will depend on receptor reserve.
我们利用放射性配体结合和功能研究，在大鼠皮层和心脏中研究了功能选择性毒蕈碱M1受体部分激动剂沙可美林[SB - 202026（R -（Z）-（+）-α -（甲氧基氨基）-1 - 氮杂双环[2.2.2]辛烷 - 3 - 乙腈）]的药理学特性。放射性配体结合研究中的奎宁环基苯甲酸酯/氧化震颤素 - M乙酸酯比值表明，沙可美林和占诺美林[3（3 - 己氧基 - 1,2,5 - 噻二唑 - 4 - 基）-1,2,5,6 - 四氢 - 1 - 甲基吡啶]是皮层和心脏膜中毒蕈碱受体部分激动剂。在大鼠皮层的[35S]GTPγS结合研究中，卡巴胆碱通过毒蕈碱M2/M4受体刺激结合，沙可美林可阻断该作用，其pA2为7.2。在大鼠心脏膜中，卡巴胆碱也通过毒蕈碱M2受体刺激[35S]GTPγS结合研究。沙可美林在大鼠和心脏组织中均引起基础[35S]GTPγS结合的小幅刺激。沙可美林不刺激大鼠皮层切片中的磷酸肌醇水解，但能阻断卡巴胆碱引起的毒蕈碱M1受体介导的反应，其表观pKb为6.9。占诺美林和米拉美林在浓度高达100μM时对磷酸肌醇水解也无影响。在大鼠心房的腺苷酸环化酶研究中，沙可美林抑制福斯高林刺激的腺苷酸环化酶活性的程度与卡巴胆碱、占诺美林和米拉美林相似。本研究采用放射性配体结合技术，支持了先前声称沙可美林是毒蕈碱受体部分激动剂的出版物。正如预期的那样，本研究表明该化合物在毒蕈碱受体亚型和不同组织中的功能作用将取决于受体储备。
