Development of highly potent vasoactive compounds.

Maxadilan（Maxa）是一种有效和持久的血管扩张剂，其已由Lerner从吸血沙蝇Lutzomyia longipalpis（利什曼病的载体）的唾液腺裂解物中分离。Maxa由61个氨基酸组成，具有两个二硫键。最近，发现Maxa是PACAP 1型受体（PAC 1）的激动剂，尽管PACAP和Maxa之间没有显著的序列相似性。PACAP属于神经肽的大家族，其通过跨越G蛋白偶联受体的成员起作用。研究GPCR的识别特性对于阐明其功能和药物开发具有重要意义。为了开发针对PAC 1的激动剂和拮抗剂，Maxa及其二硫键异构体和各种相关肽如中间、N-和C-末端片段以及中间区域缺失的Maxa已经通过高效SPPS用改进的合成方案制备，在纯化和表征后，获得的肽用于不同的生物测定，包括使用大鼠脑膜的PAC 1结合测定和最近的生物测定。开发了黑素细胞技术来阐明PAC 1识别的结构要求，特别是拮抗作用。结果表明，Maxa的中间部分和第一个二硫键不是识别所必需的。观察到中间区域缺失的Maxa片段对PAC 1的拮抗作用。

Maxadilan (Maxa) is a potent and persistent vasodilator, which has been isolated from the salivary gland lysates of the blood feeding sand fly Lutzomyia longipalpis (a vector of leishmaniasis) by Lerner. Maxa consists of 61 amino acids with two disulfide linages. More recently, Maxa was found to be an agonist of the PACAP type 1 receptor (PAC1) although there is no significant sequence similarity between PACAPs and Maxa. PACAPs belong to a large family of neuropeptides that function through members spanning G-protein-coupled receptors. Exploring the recognition characteristics of GPCRs is particular important for the elucidation of their functions and development of pharmaceuticals. To develop agonists and antagonists against PAC1 , Maxa with its disulfide isomers and various related poptides such as middle, N- and C-terminal fragments as well as middle-region deleted Maxa have been prepared by highly efficient SPPS with improved synthesis protocols, After purification and characterization the peptides obtained were used in different bioassays that include a PAC 1 binding assay using rat brain membranes and the recent developed melanophore technology to elucidate the structure requirements for PAC1 recognition, especially anatgonistic actions. The results indicated that the middle section of Maxa and the first disulfide linkage are not essential for recognition. An antagonistic action to PAC1 is observed for the middle-region deleted Maxa fragment.