ANTI-MITOGENIC BOMBESIN ANTAGONISTS

这是当前项目的重复竞争续订申请 这是NIH支持的第三个年头。它涉及到设计、合成和生物学。 蛙皮素/胃泌素释放肽(Bn/GRP)、神经介素B(NMB)和 可能对多种疾病具有治疗潜力的相关多肽类似物 它们充当自分泌生长剂的癌症形式。当前目标 主要内容如下：(1)特异性NMB激动剂和拮抗剂的开发。 NMB受体刚刚被克隆，并被发现具有完全不同的 配基识别要求。受体广泛分布于 中枢神经系统和神经末梢位于胃肠道，在某些HSCL中高表达 肿瘤，单独或与Bn/GRP受体联合使用。甚至更具体 和有效的NMB激动剂已经被制造出来，并将作为基础 对于特定的NMB拮抗剂设计。所有在场的Bn对手几乎没有 对这种受体的亲和力。(2)环状Bn多肽的进一步探索 用作激动剂/拮抗剂构象的探针。我们最近做了 发现D-Cys-Asn-Trp-Ala-Val-D-Ala-His-Leu-CysNH2是一种有效的Bn PsiCH2NH(13-14)为纯拮抗剂。 酰胺桥环[D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Leu]也是一种 具有明显结合亲和力的激动剂。这些将构成以下的基础 进一步增加亲和力和简化的环状激动剂和拮抗剂 设计。在相关工作中，讨论了新的方法和合成路线。 为某些氨基酸引入构象限制- 锁链。这些环状和受约束的结构将进行2D核磁共振 和分子建模技术，旨在微调模拟设计和 阐明受体机制。(3)受体水平进一步提高 短Bn/GRP受体的亲和力和药代动力学特性 D-F5-Phe-Asn-Trp-D-Ala-Val-Gly-His-Leu-ome等拮抗剂。(4) SARS的叶状杆菌检查--有新的证据表明 偏爱叶黄素的受体存在于哺乳动物组织中。 叶下珠蛋白在结构上与Bn/GRP和 NMB。此外，我们还将检查类似SARS的一种不寻常的大鼠尿 纯拮抗剂在其上显示激动剂活性的膀胱受体。(5) 葛根素抗肿瘤生长作用的研究进展 新的Bn/GRP和NMB类似物在体内外，特别是在人身上 小细胞肺癌、前列腺癌、乳腺癌和结肠癌，现在都是 现在已经被证明过度表达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.