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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-activity study of the nociceptin(1-13)-NH2 N-terminal tetrapeptide and discovery of a nociceptin receptor antagonist.
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Structure-activity study of the nociceptin(1-13)-NH2 N-terminal tetrapeptide and discovery of a nociceptin receptor antagonist.

机译：Nociceptin（1-13）-NH2 N-末端四肽的结构活性研究和Nociceptin受体拮抗剂的发现。

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摘要

In the present study, the minimal fragment sequence required to fully activate the nociceptin (NC) receptor, namely NC(1-13)-NH2, was used as template for the design of a series of new compounds. Changes were made in the N-terminal tetrapeptide Phe-Gly-Gly-Phe, which has been shown to be essential for receptor occupation and activation. The new compounds were tested for their ability to inhibit the electrically evoked contraction of the mouse vas deferens, a pharmacological preparation sensitive to NC. Results obtained indicate that (a) the replacement of Gly2 or Gly3 with an aromatic residue (Phe) of L or D chirality eliminates the ability of the peptide to occupy the NC receptor; (b) the distance between Phe1 and Phe4 of NC appears to be critical, since any alteration of it leads to a marked decrease or a total elimination of biological activity; and (c) the insertion of a pseudopeptide bond between Phe1 and Gly2 maintains affinity but eliminates the ability of the peptide to activate the NC receptor and leads to antagonism. The peptide [Phe1psi(CH2-NH)Gly2]-NC(1-13)-NH2 acts as a selective NC receptor antagonist and is inactive on opioid receptors. The results summarized in this paper confirm and extend our previous findings by showing that the structural requirements for NC binding to its receptor are clearly different from those of opioids; in addition, this structure-activity study has led to the identification of the first NC receptor selective antagonist.
机译：在本研究中，完全激活伤害感受素（NC）受体即NC（1-13）-NH2所需的最小片段序列被用作设计一系列新化合物的模板。 N端四肽Phe-Gly-Gly-Phe发生了变化，这已证明对受体的占领和激活至关重要。测试了这些新化合物抑制小鼠输精管的电诱发收缩的能力，所述输精管对NC敏感。获得的结果表明：（a）用L或D手性的芳族残基（Phe）替换Gly2或Gly3消除了肽占据NC受体的能力; （b）NC的Phe1和Phe4之间的距离似乎很关键，因为它的任何改变都会导致生物活性显着降低或完全消除; （c）在Phe1和Gly2之间插入假肽键保持亲和力，但是消除了肽激活NC受体的能力并导致拮抗作用。肽[Phe1psi（CH2-NH）Gly2] -NC（1-13）-NH2充当选择性NC受体拮抗剂，对阿片受体无活性。本文总结的结果证实了NC与其受体结合的结构要求明显不同于阿片类药物，从而证实并扩展了我们先前的发现。此外，这项结构活性研究还导致了第一个NC受体选择性拮抗剂的鉴定。

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