ANTIMITOGENIC BOMBESIN ANTAGONISTS

这是一个重复的竞争性续期申请的一个项目，目前在 第三个年头的支持。 它涉及设计，合成和生物学 蛙皮素/胃泌素释放肽（Bn/GRP）、神经介肽B（NMB）和 相关的肽类似物可能在许多疾病中具有治疗潜力， 它们作为自分泌生长剂的癌症形式。 当前目标 （1）特异性NMB激动剂和拮抗剂的开发。 NMB受体刚刚被克隆出来，发现它具有完全不同的 配体识别要求。 受体广泛分布于 胃肠道中的中枢神经系统和神经末梢，并且在一些HSCL中过度表达 肿瘤，单独或与Bn/GRP受体联合。 甚至更具体的 和有效的NMB激动剂已经被制造出来， 用于特定的NMB拮抗剂设计。 所有现有的Bn拮抗剂几乎没有 对这种受体的亲和力。 (2)环Bn肽的进一步探索 用作激动剂/拮抗剂构象的探针。 我们最近 发现D-Cys-Asn-Trp-Ala-Val-D-Ala-His-Leu-CysNH 2是一种有效的Bn 其psiCH 2NH（13-14）对应物是纯拮抗剂。 酰胺桥环[D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Leu]也是一种 激动剂具有可观的结合亲和力。 这些将构成基础， 进一步增加亲和力和简化的环状激动剂和拮抗剂 设计 在相关的工作中，讨论了新的方法和合成路线 用于引入对某些氨基酸侧链的构象限制， 店 这些环状和受约束的结构将经受2D NMR 和分子建模技术，旨在微调模拟设计， 阐明受体机制。 (3)受体的进一步改善 短Bn/GRP受体的亲和力和药代动力学性质 拮抗剂如D-F5-Phe-Asn-Trp-D-Ala-Val-Gly-His-Leu-OMe。 （四） 叶绿壳菌素SAR的检查-有新的证据表明， 哺乳动物组织中存在叶绿霉素偏好性受体。 叶下托蛋白与Bn/GRP和Bn/GRP两者具有重要的结构差异。 NMB。 此外，我们还将检查一种不寻常的大鼠尿液的模拟SAR。 膀胱受体，纯拮抗剂对其显示激动剂活性。 （五） 继续研究本发明的抗肿瘤生长作用， 新的Bn/GRP和NMB类似物在体外和体内，特别是在人 小细胞肺癌、前列腺癌、乳腺癌和结肠癌， 现已显示过表达Bn/GRP和/或NMB受体。

This is a repeat competitive renewal application for a project currently in its 3rd year of NIH support. It concerns the design, synthesis and biology of bombesin/gastrin releasing peptide (Bn/GRP), neuromedin B (NMB), and related peptide analogues which could have therapeutic potential in many forms of cancer where they act as autocrine growth agents. Current goals are as follows: (1) Development of specific NMB agonists and antagonists. The NMB receptor has just been cloned and found to have entirely different ligand recognition requirements. Receptors are widely distributed in the CNS and nerve endings in the GI tract and are over-expressed in some HSCL tumors, alone or in conjunction with Bn/GRP receptors. Even more specific and potent NMB agonists have already been made and will be used as a basis for specific NMB antagonist design. All present Bn antagonists have little affinity for this receptor. (2) Further exploration of cyclic Bn peptides to be used as probes of agonist/antagonist conformation. We have recently found that D-Cys-Asn-Trp-Ala-Val-D-Ala-His-Leu-CysNH2 is a potent Bn agonist and that its psiCH2NH(13-14) counterpart is a pure antagonist. Amide-bridged cyclo[D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Leu] is also an agonist with appreciable binding affinity. These will form the basis for further increases in affinity and simplified cyclic agonist and antagonist design. In related work, new approaches and synthetic routes are discussed for introducing conformational restraints for certain amino acid side- chains. These cyclic and restrained structures will be subjected to 2D NMR and molecular modelling techniques aimed at fine-tuning analogue design and elucidating receptor mechanisms. (3) Further improvement in receptor affinity and pharmacokinetic properties of short Bn/GRP receptor antagonists such as D-F5-Phe-Asn-Trp-D-Ala-Val-Gly-His-Leu-OMe. (4) Examination of phyllolitorin SARs -there is emerging evidence that phyllolitorin-preferring receptors are present in mammalian tissue. Phyllolitorin has important structural differences from both Bn/GRP and NMB. Also, we will examine analogue SARs for an unusual rat urinary bladder receptor on which pure antagonists display agonist activity. (5) Continued investigations on the anti-tumor growth effects of present and new Bn/GRP and NMB analogues in vitro and in vivo, particularly on human small cell lung carcinomas, prostate, breast and colon tumors, all ow which have now been shown to overexpress Bn/GRP and/or NMB receptors.