Address and message sequences for the nociceptin receptor: A structure-activity study of nociceptin-(1-13)-peptide amide
Address and message sequences for the nociceptin receptor: A structure-activity study of nociceptin-(1-13)-peptide amide
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DOI：
10.1021/jm970011b
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发表时间：
1997-06-06
影响因子：
7.3
通讯作者：
Regoli, D
中科院分区：
文献类型：
--
作者：
Guerrini, R;Calo, G;Regoli, D
制备了痛敏素（NC）及其部分片段以及痛敏素-（1-13）-肽酰胺[NC（1- 13）-NH 2]及其一系列类似物，并在小鼠输精管中进行了测试，试图鉴定参与痛敏素与其受体的激活（信息）和结合（地址）的序列。抑制小鼠输精管电诱发抽搐的NC受体被证明与δ阿片受体不同，因为纳洛酮和Dmt-Tic-OH（一种选择性δ阿片受体拮抗剂）阻断δ阿片受体，但对伤害感受素受体没有影响。结构-活性实验的结果表明，（a）NC的整个序列可能不是完全生物活性所必需的，因为NC（1-13）-NH 2与NC一样具有活性;（B）然而，NC的片段必须如NC（1-13）-NH 2中那样被酰胺化，以保护其不被蛋白酶降解;（c）阳离子残基（如Arg（8，12），Lys（9，13））似乎起功能作用，因为它们在NC（1-13）-NH 2序列中被Ala取代导致失活;（d）N-末端四肽Phe-Gly-Gly-Phe对于活性是必需的：其全长和柔性似乎是NC受体活化和/或占据所需的;（e）Phe（4）而不是Phe（1）似乎是参与受体活化的残基，因为用Leu替换Phe（1）没有效果，而Phe（4）导致失活。本文总结的结果表明，NC的占领和激活其受体的结构要求是不同的阿片类药物，特别是δ激动剂。
Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC(1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Args(8,12), Lys(9,13)) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe(4) and not Phe(1) appears to be the residue involved in receptor activation, since the replacement of Phe(1) with Leu has no effect, while that of Phe(4) leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.