Moreno D, Gourlet P, De Neef P, Cnudde J, Waelbroeck M, Robberecht P
Department of Biochemistry and Nutrition, Faculty of Medicine, Université Libre de Bruxelles, Bat G/E, CP 611, 808 route de Lennik, B-1070, Brussels, Belgium.
Peptides. 2000 Oct;21(10):1543-9. doi: 10.1016/s0196-9781(00)00309-0.
Ro 25-1553 is a cyclic VIP derivative with a high affinity for the VPAC(2) receptor subtype. Our goal was to identify the modifications that support its selectivity for VPAC(2) receptors, and to develop a VIP or Ro 25-1553 analog behaving as a high affinity, VPAC(2) selective antagonist. The selectivity of Ro 25-1553 for the human receptor was supported mainly by the acetylation of the amino-terminus, by the introduction of a lysine residue in position 12, and by the carboxyl-terminal extension. The lactam bridge created between positions 21 and 25 contributed to the affinity of the compound for the VIP receptors but participated only marginally to its selectivity. Deletion of the first five aminoacid residues led to a low affinity antagonist with a low selectivity. Introduction of a D-Phe residue in position 2 reduced the affinity, the selectivity and the intrinsic activity, the compound being a partial agonist. Myristoylation of the amino-terminus of [K(12)]VIP(1-26) extended carboxyl-terminally with the -K-K-G-G-T sequence of Ro 25-1553 led to a high affinity, selective VPAC(2) receptor antagonist. This molecule represents the first selective human VPAC(2) receptor antagonist described to date.
Ro 25-1553是一种对VPAC(2)受体亚型具有高亲和力的环化血管活性肠肽（VIP）衍生物。我们的目标是确定有助于其对VPAC(2)受体具有选择性的修饰，并开发一种表现为高亲和力、VPAC(2)选择性拮抗剂的VIP或Ro 25-1553类似物。Ro 25-1553对人受体的选择性主要由氨基末端的乙酰化、第12位赖氨酸残基的引入以及羧基末端的延伸所支持。21位和25位之间形成的内酰胺桥有助于该化合物对VIP受体的亲和力，但对其选择性的贡献很小。删除前五个氨基酸残基会导致一种低亲和力、低选择性的拮抗剂。在第2位引入D-苯丙氨酸残基会降低亲和力、选择性和内在活性，该化合物为部分激动剂。对[K(12)]VIP(1-26)的氨基末端进行肉豆蔻酰化，并在羧基末端延伸Ro 25-1553的-K-K-G-G-T序列，可产生一种高亲和力、选择性的VPAC(2)受体拮抗剂。该分子是迄今为止所描述的首个选择性人VPAC(2)受体拮抗剂。
