Otsuki M, Fujii M, Nakamura T, Okabayashi Y, Tani S, Fujisawa T, Koide M, Baba S
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
Dig Dis Sci. 1989 Jun;34(6):857-64. doi: 10.1007/BF01540270.
D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylami no)-5- oxopentanoic acid (CR 1505; loxiglumide) is a newly developed analog of proglumide. We examined the inhibitory effects of loxiglumide on pancreatic exocrine function in the isolated pancreatic acini and the isolated perfused pancreata of rats. Loxiglumide inhibited cholecystokinin octapeptide (CCK-8)-stimulated amylase release and, similarly, binding of [125I]CCK-8 to isolated rat pancreatic acini. Loxiglumide was about 3000 times more potent than the reference substance proglumide, but was about 1000 times less potent than L-364,718, another new CCK antagonist having benzodiazepine ring, in inhibiting CCK-8-stimulated amylase release. The inhibitory effect of loxiglumide displayed competitive kinetics and was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. The inhibitory effect of loxiglumide was fully reversible in isolated acini. However, the pancreata perfused with 10 microM loxiglumide for 20 min did not respond to CCK-8 for more than 20 min even after the removal of loxiglumide infusion. In contrast, an immediate increase in pancreatic exocrine secretion was observed after proglumide removal. Loxiglumide appeared to be bound to the receptors on acinar cells in a slowly dissociating state. These results indicate that loxiglumide acts as a potent, competitive, and specific CCK antagonist on the exocrine pancreas and, because of its prolonged inhibitory action, may be useful as a therapeutic agent in pancreatic disease.
D，L-4-（3,4-二氯苯甲酰氨基）-5-（N-3-甲氧基丙基-戊基氨基）-5-氧代戊酸（CR 1505；洛昔谷胺）是一种新开发的丙谷胺类似物。我们研究了洛昔谷胺对大鼠离体胰腺腺泡和离体灌注胰腺外分泌功能的抑制作用。洛昔谷胺抑制胆囊收缩素八肽（CCK-8）刺激的淀粉酶释放，同样也抑制[125I]CCK-8与离体大鼠胰腺腺泡的结合。在抑制CCK-8刺激的淀粉酶释放方面，洛昔谷胺的效力比参比物质丙谷胺强约3000倍，但比另一种具有苯二氮䓬环的新型CCK拮抗剂L-364,718弱约1000倍。洛昔谷胺的抑制作用呈现竞争性动力学，且对CCK具有特异性，即其他受体促分泌剂或绕过受体的药物的作用未被改变。在离体腺泡中，洛昔谷胺的抑制作用是完全可逆的。然而，用10 microM洛昔谷胺灌注胰腺20分钟后，即使在停止输注洛昔谷胺后，胰腺对CCK-8的反应在20多分钟内仍未恢复。相比之下，在停止输注丙谷胺后，胰腺外分泌立即增加。洛昔谷胺似乎以缓慢解离的状态与腺泡细胞上的受体结合。这些结果表明，洛昔谷胺在外分泌胰腺上作为一种强效、竞争性和特异性的CCK拮抗剂发挥作用，并因其延长的抑制作用，可能作为胰腺疾病的治疗药物有用。
