The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes.
The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes.
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DOI：
10.1002/mds.870010208
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发表时间：
1986-01-01
期刊：
影响因子：
--
通讯作者：
Burke, R E
中科院分区：
文献类型：
--
作者：
Burke, R E
抗胆碱能药物用于治疗许多神经系统疾病，包括帕金森病、前庭障碍和肌张力障碍。传统上，这些药物被认为以类似的方式起作用，作为一类毒蕈碱受体的竞争性拮抗剂，并且在治疗效果上没有显着差异。然而，最近的药理学研究表明，新型拮抗剂吡仑西平能够识别毒蕈碱受体之间的异质性；高亲和力的哌嗪位点被分类为M1位点，低亲和力位点被分类为M2。本研究考察了目前可用于治疗神经系统症状的抗胆碱能药物是否对这些亚型具有选择性，以及它们的选择性程度是否不同；研究表明，这些药物确实表现出选择性。所有这些都对M1位点有更大的亲和力，表明对大鼠前脑膜的亲和力更高，其中M1占主导地位，而后脑制剂中M2占主导地位。选择性的程度差别很大；一些化合物，如乙氧丙嗪，几乎没有M1选择性，而另一些化合物，如东莨菪碱、三己苯基和双苯醚，则具有很强的选择性，如吡仑平。目前尚不清楚这些选择性的差异是否有任何直接的治疗意义。然而，这些结果支持了毒蕈碱受体亚型的新兴概念和开发更具选择性的药物的前景，具有增强的治疗效果。
Anticholinergic drugs are used to treat a number of neurologic disorders, including parkinsonism, vestibular disturbances, and dystonia. Traditionally, these drugs have been thought to act in similar fashion, as competitive antagonists at a single class of muscarinic receptors, and not to differ significantly in their therapeutic efficacy. Recently, however, pharmacologic studies have shown that the novel antagonist pirenzepine is capable of recognizing heterogeneity among muscarinic receptors; high-affinity pirenzepine sites have been classified as M1 sites and low-affinity sites as M2. This study examined whether the anticholinergics currently available for treatment of neurologic symptoms have selectivity for these subtypes and whether they differ in their degree of selectivity; the study showed that these drugs do demonstrate selectivity. All had greater affinity for the M1 site, indicated by higher affinity for rat forebrain membranes, where M1 predominates, than hindbrain preparations, where M2 predominates. The degree of selectivity varied greatly; some compounds, such as ethopropazine, had little M1 selectivity, whereas others, such as scopolamine, trihexyphenidyl, and biperiden, were quite selective, like pirenzepine. It is unknown whether these differences in selectivity have any immediate therapeutic implications. However, these results support the emerging concept of muscarinic receptor subtypes and the prospect of developing more selective agents, with enhanced therapeutic efficacy.