BACKGROUND & AIMS:
:Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.
背景与目标:
:抗胆碱能药和促运动药是肠易激综合征(IBS)患者的主要治疗手段,尽管它们的疗效有限且副作用严重。这些药物的临床局限性是它们与各种受体的相对广泛和非特异性药理相互作用的结果。肠道生理学的最新进展已导致鉴定可能在IBS发病机理中起关键作用的各种受体靶标。寻求安全有效的IBS治疗的药物化学家正在开发针对许多这些特定受体的化合物。最新一代的抗胆碱能药,例如扎米芬那,达利福星和YM-905,可提供对毒蕈碱3型受体的选择性拮抗作用。 Tegaserod是一种选择性5-HT4部分激动剂,已在多项临床试验中进行了测试,可有效减轻腹痛,腹胀和便秘的症状。 Ezlopitant和nepadudant分别是1型和2型神经激肽受体的选择性拮抗剂,在减少肠道蠕动和疼痛方面显示出希望。 Loperamide是一种mu(mu)阿片类受体激动剂,对于腹泻为主要肠综合征的IBS腹泻患者(IBS-D)是安全有效的。 Fedotozine是一种κ(阿片)阿片受体激动剂,已在各种临床试验中用作内脏镇痛剂,但结果相矛盾。 Alosetron是5-HT3受体拮抗剂,已在IBS-D患者中显示出疗效,但上市后随访中发现的缺血性结肠炎事件导致其退出市场。靶向胆囊收缩素的化合物。 A,N-甲基-D-天门冬氨酸,α2-肾上腺素和促肾上腺皮质激素释放因子受体也进行了审查。