NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

这些研究的初始阶段涉及体内中枢 神经肽对胃酸分泌的影响。高潮 亲和力MU选择性阿片七肽地吗啡产生显著 抑制清醒大鼠胃酸分泌。这一效果 被先前给药的消炎痛阻断，这表明 前列腺素的合成是抑制作用所必需的 神经肽对胃液分泌的影响。这些数据与 临床研究表明，正在接受治疗的个人 吗啡类止痛药显示出较低的溃疡发生率 胃的粘膜衬里。这些结果导致了第二阶段： 德吗啡与脑膜相互作用的受体分析 结合部位。有约束力的数据提供了关于 受体与选择性阿片肽相互作用的新模型 (1)Tyr5的缺失或被亲水性残基取代，被破坏 在Mu和Delta受体位置上的识别；(2)阻断 Tyrl上的官能团类似地减少了结合；(3)加成 Ser7上的疏水保护基团增加了对Mu和Mu的亲和力 Delta位点，但降低了MU选择性；以及(4)对D的需求 残基2的a碳构型及其酰胺化反应 C-末端残基是必需的。这个模型提出了Mu受体 容纳两个结合口袋：T(Mu)位置用于堆叠的Tyr1/Tyr5 残基和Phe 3残基的P(Mu)位，它从 多肽的骨架。Phe3-Gly4二肽区的反转 脑啡肽中Gly3-Phe4序列的去吗啡显著减少 MU选择性。因此，N-末端序列H-Tyr-D-Ala-Phe-Gly， 粒子在贝塔中通过内部氢键转变，并构成 多肽的消息域。

The initial phases of these studies involved the in vivo central administration of neuropeptides on gastric acid secretion. The high affinity mu selective opioid heptapeptide dermorphin produced marked suppression of the secretion of gastric acid in conscious rats. This effect was blocked by the prior administration of indomethacin, which suggests that the synthesis of prostaglandins is required for the inhibitory action of neuropeptides on gastric secretion. These data are in accord with clinical studies which showed that individuals being treated with morphinomimetric analgesic drugs exhibit a lower incidence of ulcers in the mucosal lining of the stomach. These results led to the second phase: receptor analyses of the interaction of dermorphin with brain membrane binding sites. The binding data provided information on the formulation of a new model for the receptor interaction with selective opioid peptides: (1) deletion of Tyr5 or replacement by a hydrophilic residue, disrupted recognition at both mu and delta receptor sites; (2) blockage of the functional groups on Tyrl similarly reduced binding; (3) addition of hydrophobic protective groups on Ser 7 increased the affinity to mu and delta sites, but decreased mu selectivity; and (4) the requirement for a D configuration about the a carbon of residue 2 and amidation of the C-terminal residue is essential. This model proposes that the mu receptor accommodates two binding pockets: a T(mu) site for the stacked Tyr1/Tyr5 residues and a P(mu) site for the Phe 3 residue, which extends outward from the peptide backbone. Reversal of the Phe3-Gly4 dipeptide region in dermorphin to the Gly3 -Phe4 sequence in enkephalin drastically diminished mu selectivity. Thus, the N-terminal sequence, H-Tyr-D-Ala-Phe-Gly, particulates in a beta-turn through internal hydrogen bonds and constitutes the message domain of the peptide.