Darker J G, Brough S J, Heath J, Smart D
Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM 19 5AW, UK.
J Pept Sci. 2001 Nov;7(11):598-605. doi: 10.1002/psc.359.
Analogues of the nonselective bombesin receptor synthetic agonist H-D-Phe-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2 were prepared and their biological activity assessed at the NMB-preferring/bombesin receptor (NMB-R: BB1), the GRP-preferring/bombesin receptor (GRP-R: BB2) and the orphan receptor bombesin receptor subtype-3 (BRS-3; BB3). Progressive N-terminal deletions identified the minimum C-terminal sequences required for maintaining a significant agonist effect, whilst an alanine scan, targeted changes in stereochemistry and other pertinent substitutions identified key side-chain and stereochemical requirements for activation. Key structural elements required for functional potency at BB1 BB2 and BB3, and for selectivity between these receptor subtypes were established. Synthetic peptides were discovered. which were highly potent agonists at BB2 and extremely selective over both BB1 and BB3.
制备了非选择性蛙皮素受体合成激动剂H-D-苯丙氨酸-谷氨酰胺-色氨酸-丙氨酸-缬氨酸-β丙氨酸-组氨酸-苯丙氨酸-异亮氨酸-酰胺的类似物，并在偏好神经降压素的/蛙皮素受体（NMB-R：BB1）、偏好胃泌素释放肽的/蛙皮素受体（GRP-R：BB2）和孤儿受体蛙皮素受体亚型-3（BRS-3；BB3）上评估了它们的生物活性。逐步的N端缺失确定了维持显著激动剂效应所需的最小C端序列，而丙氨酸扫描、立体化学的靶向改变和其他相关取代确定了激活所需的关键侧链和立体化学要求。确定了在BB1、BB2和BB3上发挥功能效力以及这些受体亚型之间选择性所需的关键结构元件。发现了合成肽，它们是BB2上的高效激动剂，并且对BB1和BB3都具有极高的选择性。
