Development of highly potent vasoactive compounds.

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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.