BINDING AND FUNCTIONAL PROFILES OF THE SELECTIVE M1 MUSCARINIC RECEPTOR ANTAGONISTS TRIHEXYPHENIDYL AND DICYCLOMINE
BINDING AND FUNCTIONAL PROFILES OF THE SELECTIVE M1 MUSCARINIC RECEPTOR ANTAGONISTS TRIHEXYPHENIDYL AND DICYCLOMINE
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DOI：
10.1111/j.1476-5381.1986.tb11123.x
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发表时间：
1986-09-01
影响因子：
7.3
通讯作者：
MONTAGNA, E
中科院分区：
文献类型：
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作者：
GIACHETTI, A;GIRALDO, E;MONTAGNA, E
毒蕈碱受体拮抗剂双环明和三己苯酯的选择性已经在结合和功能研究中进行了检查，并与吡伦齐平和阿托品进行了比较。2在皮质膜上[3H]-pirenzepine标记的竞争实验中显示，双环明、三己苯酰基和匹伦齐平对M1毒毒碱受体亚型的亲和力最高。它们的亲和值范围较窄（3.7 ~ 14 nM），接近阿托品（1.6 nM）。心脏和腺（唾液）膜对[3H]- n -甲基东莨菪碱的竞争实验揭示了所检查药物之间的差异。二环胺、三己苯基和匹伦齐平对心脏受体的亲和力较低，对腺体受体的亲和力为中等。因此，这些药物似乎可以区分M1（皮质）和外周毒蕈碱亚型（心脏和腺体）。然而，阿托品对两种亚型的亲和性相似，ic50仅略有变化（1.6-4.6 nM）。选择性排序为：匹伦西平b>二环环明b>三己苯基>阿托品。4 .与结合数据相一致的是，匹伦西平、双环明和三己苯基在抑制m1受体介导的神经节反应（骨髓大鼠的mcna -343升压作用和猫的烟膜收缩作用）方面的能力比抑制心脏和心血管平滑肌的外周毒毒碱反应（大鼠和猫的迷走性心动过缓和猫的迷走性血管舒张）的能力强10倍。迄今为止研究的毒蕈碱拮抗剂可分为两类。三己苯基、二环胺和吡伦齐平，包括在一组中，其特点是对神经元（M1）毒蕈碱受体具有更高的亲和力，因此它们拮抗M1亚型介导的功能反应。阿托品，另一组的成员，基本上没有选择性。M1和外周毒蕈碱受体亚型的分化似乎不局限于三环类药物，如吡仑西平，而是多种化学结构共有的特性。在毒蕈碱受体亚型的分类中，三己苯基和双环胺似乎都是有用的药理学工具。
1 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. 2 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). 3 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 > dicyclomine > trihexyphenidyl > atropine. 4 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). 5 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.