BOMBESIN ANTAGONIST ANALOGS

蛙皮素及其哺乳动物对应物胃泌素释放肽， 普遍存在的神经胃肠肽组的成员， 分布于中枢神经系统、肺和胃肠道。 主要生物 活性包括可能通过以下途径有效刺激胃泌素释放： 直接作用于胃泌素产生细胞，刺激胰腺酶 释放和刺激垂体GH释放。 最近已经 显示人肺燕麦细胞癌分泌并含有大量 蛙皮素样肽，并已提出，蛙皮素可能是一种 这些肿瘤的生长因子，也负责许多 疾病产生的副作用。 我们建议进行 C-末端的合成类似物的结构-活性研究 蛙皮素的八肽区，似乎是最短的片段， 保持完整的生物活性。 该项目的主要目标是 以开发该肽的有效竞争性拮抗剂。 不仅会 这些化合物在阐明许多生理学方面具有巨大的价值， 蛙皮素的作用和机制，但也可能是潜在的 在控制某些肺癌生长中的治疗用途 与蛙皮素分泌过多相关的副作用。 也是 拮抗剂可能会提供一种新的控制途径， 胃酸分泌也有一定的治疗意义。 蛙皮素类似物将通过自动化固相方法合成， 通过制备型HPLC纯化，并在体外测定对释放的影响 淀粉酶从分散的大鼠腺泡细胞和体内的影响， 免疫反应性胃泌素释放也在大鼠中。 影响的研究 蛙皮素及其拮抗剂对其它几种肽释放的影响 也考虑激素。

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.