Gozes I, Lilling G, Glazer R, Ticher A, Ashkenazi I E, Davidson A, Rubinraut S, Fridkin M, Brenneman D E
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
J Pharmacol Exp Ther. 1995 Apr;273(1):161-7.
To distinguish vasoactive intestinal peptide (VIP) receptors in the brain-mediating neurotransmission and neurotrophism, potent VIP analogues were designed. Using a single amino acid substitution and the addition of a fatty acyl moiety, an analogue was devised that exhibited both a 100-fold greater potency than VIP and specificity for a VIP receptor associated with neuronal survival. This VIP agonist increased neuronal survival via a cAMP-independent mechanism. Identical chemical modification of a prototype VIP antagonist (Met-Hybrid, Neurotensin6-11-VIP7-28) also resulted in a 100-fold greater potency in blocking VIP-mediated increases in neuronal survival. Blockade of circadian activity rhythms was limited to VIP antagonists that could inhibit VIP-mediated increases in cAMP. These lipophilic peptides provide novel tools in receptor discrimination and drug design.
为了区分介导神经传递和神经营养作用的大脑中的血管活性肠肽（VIP）受体，设计了强效的VIP类似物。通过单个氨基酸取代和添加脂肪酰基部分，设计出一种类似物，其效力比VIP高100倍，并且对与神经元存活相关的VIP受体具有特异性。这种VIP激动剂通过一种不依赖cAMP的机制增加神经元存活。对原型VIP拮抗剂（Met-Hybrid，神经降压素6-11-VIP7-28）进行相同的化学修饰，在阻断VIP介导的神经元存活增加方面也产生了100倍的效力提升。昼夜活动节律的阻断仅限于能够抑制VIP介导的cAMP增加的VIP拮抗剂。这些亲脂性肽为受体鉴别和药物设计提供了新工具。
