BOMBESIN ANTAGONIST ANALOGS

Bombein和它的哺乳动物对应的胃泌素释放肽 无处不在的神经胃肠肽的成员，是 分布于中枢神经系统、肺部和胃肠道。主要生物学 活动包括有效刺激胃泌素的释放，可能是通过 直接作用于胃泌素产生细胞，刺激胰酶 释放，并刺激脑垂体GH的释放。最近，它一直在 显示人类肺燕麦细胞癌分泌并含有大量 蛙皮素样多肽，有研究表明蛙皮素可能是一种 这些肿瘤的生长因子，也是导致许多 这种疾病造成的副作用。我们建议开展 C-末端合成类似物的构效关系研究 蛙皮素的八肽区域，它似乎是最短的片段 保持充分的生物活性。这个项目的主要目标是 开发该肽的强有力的竞争性拮抗剂。不仅会 这些化合物在阐明许多生理上的 蛙皮素的作用和作用机制，但也可能是潜在的 治疗在某些肺癌生长控制中的应用 与蛙皮素过度分泌相关的副作用。它也是 一个拮抗者可能会提供一种新的方法来控制 胃酸分泌，这也有一定的治疗意义。 蛙毒素类似物将通过自动固相方法合成， 制备高效液相色谱分离纯化，体外释放度考察 从分散的大鼠腺泡细胞中提取淀粉酶并在体内对其影响 免疫反应性胃泌素释放也在大鼠体内。对影响的研究 蛙皮素及其拮抗剂对其他几种多肽释放的影响 荷尔蒙也被考虑在内。

Bombesin and its mammalian counterpart, gastrin releasing peptide, are members of the group of ubiquitous neurogastrointestinal peptides and are distributed throughout the CNS, lungs, and GI tract. Principal biological activities include potent stimulation of gastrin release, probably by direct action on gastrin-producing cells, stimulation of pancreatic enzyme release, and stimulation of pituitary GH release. Recently it has been shown that human lung oat cell carcinomas secrete and contain large amounts of bombesin-like peptide and it has been suggested that bombesin could be a growth factor for these tumors and also responsible for many of the side-effects created by the disease. We propose to carry out structure-activity studies on synthetic analogs of the C-terminal octapeptide region of bombesin which appears to be the shortest fragment to retain full biological activity. The primary aim of this project would be to develop potent competitive antagonists of the peptide. Not only would such compounds be of enormous value in elucidating the many physiological roles and mechanisms of action of bombesin, but could also be of potential therapeutic use in the control of growth of certain lung cancers and the side-effects associated with hypersecretion of bombesin. It is also possible that an antagonist would offer a novel route for control of gastric acid secretion which also has some therapeutic implications. Bombesin analogs will be synthesized by automated solid-phase methods, purified by preparative HPLC, and assayed in vitro for effects on release of amylase from dispersed rat acinar cells and in vivo for effects on immunoreactive gastrin release also in the rat. Studies of the effects of bombesin and its antagonists on the release of several other peptide hormones are also contemplated.