The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound
The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound
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DOI：
10.1016/s0014-2999(01)01087-1
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发表时间：
2001-06-29
影响因子：
5
通讯作者：
Schuurkes, JAJ
中科院分区：
文献类型：
--
作者：
Briejer, MR;Bosmans, JP;Schuurkes, JAJ
普芦卡必利是一种新型肠动力化合物，是苯并呋喃类的第一个代表。我们着手在各种受体结合和器官浴实验中建立其药理学特征。受体结合数据表明普卡必利对两种研究的 5-HT4 受体亚型具有高亲和力，人 5-MT4a 和 5-MT4b 受体的平均 pK(i) 估计值分别为 8.60 和 8.10。在本研究中研究的 50 种其他结合测定中，只有人类 D-4 受体 (pK(i) 5.63)、小鼠 5-HT3 受体 (pK(i) 5.41) 和人类 sigma (i) (pK(i) 5.43) 显示出可测量的亲和力，导致对 5-HT4 受体的选择性至少为 290 倍。经典的器官浴实验是使用来自大鼠、豚鼠和狗胃肠道的分离组织，采用各种方案进行的。普芦卡必利是豚鼠结肠中的 5-HT4 受体激动剂，因为它诱导收缩（pEC(50) = 7.48 +/- 0.06；对 5-HT2A 或 5-HT3 受体拮抗剂不敏感，但被 5-HT4 受体拮抗剂抑制）以及促进电刺激诱导的非胆碱能收缩（被 5-HT4 受体阻断）对手）。此外，它以 5-HT4 受体拮抗剂敏感的方式引起大鼠食道制剂的松弛 (pEC(50) = 7.81 +/- 0.17)。普芦卡必利在高达 10 muM 时不会引起 5-HT2A、5-HT2B 或 5-HT3、胃动素或胆囊收缩素 (CCK) 受体介导的收缩的相关抑制，也不会引起烟碱或毒蕈碱乙酰胆碱受体介导的收缩的相关抑制。结论是普卡必利是一种有效的、选择性的、特异性的5-HT4受体激动剂。由于其用于治疗肠道动力障碍，重要的是要注意普卡必利缺乏抗胆碱能、抗胆碱酯酶或非特异性抑制活性，并且不会拮抗 5-HT2A、5-HT2B 和 5-MT3 受体或胃动素或 CCK 受体。 (C) 2001 年由 Elsevier Science B.V. 出版
Prucalopride is a novel enterokinetic compound and is Be first representative of the benzofuran class. We set out to establish its pharmacological profile in various receptor binding and organ bath experiments. Receptor binding data have demonstrated prucalopride's high affinity to both investigated 5-HT4 receptor isoforms, with mean pK(i) estimates of 8.60 and 8.10 for the human 5-MT4a and 5-MT4b receptor, respectively. From the 50 other binding assays investigated in this study only the human D-4 receptor (pK(i) 5.63), the mouse 5-HT3 receptor(pK(i) 5.41) and the human sigma (i) (pK(i) 5.43) have shown measurable affinity, resulting in at least 290-fold selectivity for the 5-HT4 receptor. Classical organ bath experiments were done using isolated tissues from the rat, guinea-pig and dog gastrointestinal tract, using various protocols. Prucalopride was a 5-HT4 receptor agonist in the guinea-pig colon, as it induced contractions (pEC(50) = 7.48 +/- 0.06; insensitive to a 5-HT2A or 5-HT3 receptor antagonist, but inhibited by a 5-HT4 receptor antagonist) as well as the facilitation of electrical stimulation-induced noncholinergic contractions (blocked by a 5-HT4 receptor antagonist). Furthermore, it caused relaxation of a rat oesophagus preparation (pEC(50) = 7.81 +/- 0.17), in a 5-HT4 receptor antagonist sensitive manner. Prucalopride did not cause relevant inhibition of 5-HT2A, 5-HT2B, or 5-HT3, motilin or cholecystokinin (CCK,) receptor-mediated contractions, nor nicotinic or muscarinic acetylcholine receptor-mediated contractions, up to 10 muM. It is concluded that prucalopride is a potent, selective and specific 5-HT4 receptor agonist. As it is intended for treatment of intestinal motility disorders, it is important to note that prucalopride is devoid of anti-cholinergic, anticholinesterase or nonspecific inhibitory activity and does not antagonise 5-HT2A, 5-HT2B and 5-MT3 receptors or motilin or CCK, receptors. (C) 2001 Published by Elsevier Science B.V.