Giachetti A, Giraldo E, Ladinsky H, Montagna E
Br J Pharmacol. 1986 Sep;89(1):83-90. doi: 10.1111/j.1476-5381.1986.tb11123.x.
The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexyphenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine. Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M1 muscarinic receptor subtype as revealed in competition experiments against [3H]-pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7-14 nM) approaching that of atropine (1.6 nM). Competition experiments against [3H]-N-methylscopolamine in cardiac and glandular (salivary) membranes revealed differences between the drugs examined. Dicyclomine, trihexyphenidyl and pirenzepine displayed low affinity for the cardiac and intermediate affinity for the glandular receptors. Thus, the drugs appeared to discriminate between the M1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6-4.6 nM). The rank order of selectivity was: pirenzepine greater than dicyclomine greater than trihexyphenidyl greater than atropine. Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M1-receptor mediated ganglionic responses (McN A-343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally-induced vasodilatation in cats). The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (M1) muscarinic receptor, hence they antagonize functional responses mediated by the M1 subtype. Atropine, a member of the other group, shows essentially no selectivity. 6 Differentiation of M1 and peripheral muscarinic receptor subtypes appears to be a property not confined to tricyclics such as pirenzepine but shared by diverse chemical structures. Both trihexyphenidyl and dicyclomine appear to be useful pharmacological tools in the classification of muscarinic receptor subtypes.
已通过结合和功能研究检测了毒蕈碱受体拮抗剂双环维林和苯海索的选择性概况，并与哌仑西平和阿托品进行了比较。在针对[³H] - 哌仑西平标记的皮质膜的竞争实验中，双环维林、苯海索和哌仑西平对M1毒蕈碱受体亚型表现出最高亲和力。它们的亲和力值处于较窄范围（3.7 - 14 nM），接近阿托品的亲和力值（1.6 nM）。在心脏和腺体（唾液腺）膜中针对[³H] - N - 甲基东莨菪碱的竞争实验揭示了所检测药物之间的差异。双环维林、苯海索和哌仑西平对心脏受体显示出低亲和力，对腺体受体显示出中等亲和力。因此，这些药物似乎能够区分M1（皮质）和外周毒蕈碱亚型（心脏和腺体）。然而，阿托品对两种亚型显示出相似的亲和力，IC50值仅略有变化（1.6 - 4.6 nM）。选择性的顺序为：哌仑西平＞双环维林＞苯海索＞阿托品。与结合数据一致，哌仑西平、双环维林和苯海索在抑制M1受体介导的神经节反应（在脊髓麻醉大鼠中McN A - 343升压作用以及在猫中瞬膜收缩）方面的能力比抑制心脏和心血管平滑肌中的外周毒蕈碱反应（在大鼠和猫中的迷走性心动过缓以及在猫中的迷走神经诱导的血管舒张）高十倍。迄今为止所检测的毒蕈碱拮抗剂可分为两组。苯海索、双环维林和哌仑西平归为一组，其特点是对神经元（M1）毒蕈碱受体具有更高亲和力，因此它们拮抗由M1亚型介导的功能反应。阿托品属于另一组，基本上没有选择性。M1和外周毒蕈碱受体亚型的区分似乎不仅是哌仑西平这类三环类药物的特性，而是多种化学结构所共有的。苯海索和双环维林似乎都是用于毒蕈碱受体亚型分类的有用药理学工具。
