Gourlet P, Rathé J, De Neef P, Cnudde J, Vandermeers-Piret M C, Waelbroeck M, Robberecht P
Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Eur J Pharmacol. 1998 Jul 31;354(1):105-11. doi: 10.1016/s0014-2999(98)00435-x.
Stearyl vasoactive intestinal polypeptide has been reported to be a VIP (vasoactive intestinal polypeptide) receptor agonist of high potency with an original bioavailability and action. We synthesized three fatty acyl derivatives, myristyl-, palmityl- and stearyl-[Nle17]VIP, and tested their capacity to recognize recombinant rat- and human VIP1- and VIP2/PACAP (pituitary adenylate cyclase-activating polypeptide) receptors and to stimulate adenylate cyclase activity. The three lipophilic analogues bound with high affinity (from 0.5 to 20 nM) to both receptor subtypes but did not distinguish between them. In preparations expressing a high density of human VIP1/PACAP receptors, the three lipophilic analogues had the same efficacy as VIP and [Nle17]VIP. In preparations expressing the rat receptors, stearyl-[Nle17]VIP had a lower efficacy than the other peptides tested. In preparations expressing a low level of VIP1/PACAP receptors and in those expressing VIP2/PACAP receptors, all analogues behaved like partial agonists. The lowest efficacy was observed for stearyl-[Nle17]VIP on the VIP2/PACAP receptor subclass. Based on our results, a complex pattern of in vivo biological effects of the lipophilic VIP derivatives should be expected: these compounds might behave as full agonists, partial agonists, or antagonists of the VIP response, depending on the number and the subtype of receptor expressed.
据报道，硬脂酰血管活性肠肽是一种具有原始生物利用度和作用的高效血管活性肠肽（VIP）受体激动剂。我们合成了三种脂肪酰基衍生物，肉豆蔻酰基 -、棕榈酰基 - 和硬脂酰基 - [Nle17]VIP，并测试了它们识别重组大鼠和人类VIP1及VIP2/垂体腺苷酸环化酶激活肽（PACAP）受体的能力以及刺激腺苷酸环化酶活性的能力。这三种亲脂性类似物以高亲和力（0.5至20 nM）与两种受体亚型结合，但无法区分它们。在表达高密度人类VIP1/PACAP受体的制剂中，这三种亲脂性类似物与VIP和[Nle17]VIP具有相同的效力。在表达大鼠受体的制剂中，硬脂酰基 - [Nle17]VIP的效力低于其他测试肽。在表达低水平VIP1/PACAP受体的制剂以及表达VIP2/PACAP受体的制剂中，所有类似物均表现为部分激动剂。在VIP2/PACAP受体亚类上，硬脂酰基 - [Nle17]VIP的效力最低。根据我们的结果，预计亲脂性VIP衍生物在体内会产生复杂的生物学效应模式：这些化合物可能表现为VIP反应的完全激动剂、部分激动剂或拮抗剂，这取决于所表达受体的数量和亚型。
