Muscarinic antagonists in development for disorders of smooth muscle function
Muscarinic antagonists in development for disorders of smooth muscle function
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DOI：
10.1016/s0024-3205(98)00585-2
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发表时间：
1999-01-08
期刊：
影响因子：
6.1
通讯作者：
Napier, CM
中科院分区：
文献类型：
--
作者：
Wallis, RM;Napier, CM
多年来，对毒蕈碱Ms受体具有高亲和力的化合物已用于治疗与平滑肌张力或收缩性改变相关的病症，例如急迫性尿失禁、肠易激综合征或慢性阻塞性气道疾病。与非选择性化合物相比，Ms选择性拮抗剂具有改善耐受性的潜力。达非那新对人类克隆的毒蕈碱Mg受体具有高亲和力（pKi 9.12）和选择性（9至74倍）。与该特征一致，该化合物有效抑制Mg受体介导的平滑肌制备物（豚鼠回肠、气管和膀胱，pA（2）8.66至9.4）的反应，选择性超过通过Mi（pA（2）7.9）和Mt受体（pA（2）7.48）介导的反应。有趣的是，达非那新也表现出对肠道平滑肌的功能组织选择性超过唾液腺。在一系列动物模型中证实了达非那新的Mj相对于MI和Ma的选择性。特别是，在清醒的狗中，达非那新在低于抑制胃酸分泌（M-1反应）、增加心率（M-2反应）或抑制唾液分泌的剂量下抑制肠蠕动。临床研究正在进行中，以确定与非选择性药物相比，达非那新是否具有改善的疗效和/或耐受性。
Compounds with high affinity for muscarinic Ms receptors have been used for many years to treat conditions associated with altered smooth muscle tone or contractility such as urinary urge incontinence, irritable bowel syndrome or chronic obstructive airways disease. Ms selective antagonists have the potential for improved toleration when compared with non-selective compounds. Darifenacin has high affinity (pKi 9.12) and selectivity (9 to 74-fold) for the human cloned muscarinic Mg receptor. Consistent with this profile, the compound potently inhibited Mg receptor mediated responses of smooth muscle preparations (guinea pig ileum, trachea and bladder, pA(2) 8.66 to 9.4) with selectivity over responses mediated through the Mi (pA(2) 7.9) and Mt receptors (pA(2) 7.48). Interestingly, darifenacin also exhibited functional tissue selectivity for intestinal smooth muscle over the salivary gland. The Mj over MI and Ma selectivity of darifenacin was confirmed in a range of animal models. In particular, in the conscious dog darifenacin inhibited intestinal motility at doses lower than those which inhibit gastric acid secretion (M-1 response), increase heart rate (M-2 response) or inhibit salivary secretion. Clinical studies are ongoing to determine if darifenacin has improved efficacy and or toleration when compared with non-selective agents.