NEUROPEPTIDES: MOLECULAR MECHANISM OF ACTION

德吗啡(DM)，一种两栖阿片类七肽，含有 2位天然D-丙氨酸，N-末端DM类似物及系列 二聚体DM类似物(通过C-末端偶联)是 大鼠脑内Mu和Delta受体亲和力的分析 突触体。结合试验用~3H-DAGO测定MU受体和 β受体的3HDADLE(在N-Me-Me存在下进行) Phe3，D-Pro4)吗啡抑制与Mu-2的相互作用 受体)。二聚体DM四肽与Mu-2相互作用弱 受体；特别是具有12个亚甲基单元的类似物 多肽链之间的桥联具有较差的Mu和Delta亲和力 而且没有选择性。然而，与乙烯桥类似 含有D-Arg2和Sar4具有高的Mu亲和力、Mu选择性， 与抑制胃酸分泌有关。全 二聚体DM五肽具有很高的表观亲和力， 中等至低的MU选择性，但呈正相关 对胃液分泌的抑制。鉴于D-Arg和Sar 增加了二聚体四肽中的MU亲和力和选择性， 他们降低了五肽中的这些参数。二聚体DM DM对Mu受体具有较高的亲和力和选择性 接近DAG0，与抑制性呈正相关 在胃分泌过程中的作用。作为对 结合特异性，(L-阿拉斯加)DM类似物被测试：它结合 对亲和力小于3个数量级的Mu受体 DM，这与其最低生物活性是一致的。因此，这些 研究表明，大脑中的高亲和力Mu受体 组织与胃的抑制呈正相关 中枢(Icv)给药引起的胃酸排出量 和精选的二聚体DM类似物。

Dermorphin (DM), an amphibian opioid heptapeptide which contains a natural D-Ala in position 2, N-terminal DM analogues and a series of dimeric DM analogues (coupled through the C-terminus) were analyzed for mu- and delta-receptor affinities on rat brain synaptosomes. Binding assays used 3H-DAGO for mu-receptors and 3HDADLE for delta-receptors (carried out in the presence of (N-Me- Phe3,D-Pro4) morphiceptin to suppress interaction with mu- receptors). Dimeric DM tetrapeptides weakly interacted with mu- receptors; in particular, the analogue with a 12 methylene unit bridge between peptide chains had poor mu- and delta-affinities and no selectivity. However, analogue with an ethylene bridge containing D-Arg2 and Sar4 had high mu-affinity, mu-selectivity, and correlated to the inhibition of gastric acid secretion. All the dimeric DM pentapeptides had very high mu-affinities, with moderate to low mu-selectivity, but correlated in a positive manner to the suppression of gastric secretion. Whereas D-Arg and Sar increased mu-affinity and selectivity in the dimeric tetrapeptides, they decreased these parameters in the pentapeptides. Dimeric DM and DM exhibited high affinity for mu-receptors and selectivity approaching DAG0 and had a positive correlation to the inhibitory effect in the gastric secretory process. As a control for the binding specificity, the (L-Ala2)DM analogue was tested: it bound to mu-receptors with an affinity 3-orders of magnitude less than DM, which is in keeping with its minimal bioactivity. Thus, these studies provide evidence that high affinity mu-receptors in brain tissue correlate in a positive manner to the inhibition of gastric acid output in stomach by the central (icv) administration of DM and selected dimeric DM analogues.