Novel developments with selective, non-peptidic kappa-opioid receptor agonists.
Novel developments with selective, non-peptidic kappa-opioid receptor agonists.
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DOI：
10.1517/13543784.6.10.1351
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发表时间：
1997-10-01
影响因子：
6.1
通讯作者：
Gottschlich, R
中科院分区：
文献类型：
--
作者：
Barber, A;Gottschlich, R
尽管最近推出了一些新化合物，但最近制药公司对开发中枢活性的、选择性的kappa阿片激动剂用于治疗目的的兴趣有所降温。这反映在一些临床试验的中断上，原因通常不是外部观察者完全清楚的。螺妥林和依那多林显然已被放弃作为潜在的镇痛剂，因为它们在手术后疼痛模型中引起剂量限制性的中枢副作用(即烦躁不安)。硝沃林作为水乳剂用于治疗伴有腹水和其他低钠血症的肝硬变的开发也已停止。依那多林可能还会被用于治疗缺血性中风和严重的头部损伤，可能是在精神副作用被认为无关紧要的昏迷患者中，而阿帕多林和TRK 820仍处于癌症疼痛的第二阶段临床试验。外周选择性kappa激动剂阿西多林和非典型化合物非多津在人体内耐受性良好。然而，非多津治疗肠易激综合征和消化不良的第三阶段试验结果最终令人失望，而阿西莫林目前正处于治疗风湿性和骨关节炎引起的疼痛的第二阶段临床试验。人们热切地期待着这些试验的结果。
Despite the recent introduction of a number of new compounds, there has of late been a cooling of interest by pharmaceutical companies in the development of centrally-active, selective kappa opioid agonists for therapeutic purposes. This is reflected in the discontinuation of a number of clinical trials, for reasons that are often not completely clear to outside observers. Spiradoline and enadoline have apparently been abandoned as potential analgesics because they induce dose-limiting central side-effects (i.e., dysphoria) in models of post-surgical pain. The development of niravoline as an aquaretic for the treatment of cirrhosis with ascites and other hyponatraemic disorders has also been halted. Enadoline may yet find some application against ischaemic stroke and severe head injury, presumably in comatose patients in whom psychiatric side-effects are taken to be immaterial, while apadoline and TRK 820 remain in Phase II clinical testing against cancer pain. The peripherally-selective kappa agonists, asimadoline, and the atypical compound, fedotozine, are well-tolerated in man. Results of Phase III trials of fedotozine against irritable bowel syndrome and dyspepsia have, however, ultimately been disappointing, whereas asimadoline is currently in Phase II clinical trials against pain of rheumatic and osteoarthritic origin. The results of these trials are eagerly awaited.