Antinociceptive analogs of orphanin FQ/nociceptin(1-11).
Antinociceptive analogs of orphanin FQ/nociceptin(1-11).
复制标题
孤啡肽 FQ/伤害感受素 (1-11) 的抗伤害感受类似物。
DOI：
10.1016/s0024-3205(98)00358-0
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发表时间：
1998
期刊：
影响因子：
6.1
通讯作者：
Pasternak,GW
中科院分区：
文献类型：
--
作者：
Mathis,JP;Goldberg,IE;Rossi,GC;Leventhal,L;Pasternak,GW
在FQ/伤害感受素（OFQ/N）肽（ORL 1 KOR-3受体的内源性配体）中，存在碱性氨基酸对，这提高了加工可能产生重要的截短肽（包括OFQ/N（1-11））的可能性。OFQ/N（1-11）在体内具有抗肿瘤活性，其效价与OFQ/N相当。已合成了几种含酪氨酸的OFQ/N（1-11）类似物，并检测了其抗伤害感受活性。与OFQ/N（1-11）一样，[Tyr 1]OFQ/N（1-11）、[Tyr 10]OFQ/N（1-11）和[IodoTyr 10]OFQ/N（1-11）在小鼠甩尾试验中具有抗伤害感受性。酪氨酸类似物显示与OFQ/N（1-11）类似的效力，但作用持续时间更长。这种反应很容易逆转阿片类药物拮抗剂纳洛酮，尽管这些类似物在阿片受体的亲和力差。另一种化合物[Tyr 11]OFQ/N（1-11）具有高度致癫痫性，在与其他类似物相当的剂量下，在超过50%的受试小鼠中诱导纳洛酮敏感性癫痫发作。这些结果表明，有可能制备镇痛OFQ/N（1-11）类似物。[IodoTyr 10]OFQ/N（1 - 11）的活性表明，它可以证明可用作探索潜在OFQ/N（1-11）结合位点的放射性配体。
The presence of pairs of basic amino acids within the sequence of orphanin FQ/nociceptin (OFQ/N) peptide, the endogenous ligand for the ORL1KOR-3 receptor, has raised the possibility that processing might generate pharmacologically important truncated peptides, including OFQ/N(1–11). OFQ/N(1–11) is pharmacologically active in vivo with a potency comparable to OFQ/N. Several tyrosine-containing analogs of OFQ/N(1–11) have been synthesized and examined for antinociceptive activity. Like OFQ/N(1–11), [Tyr1]OFQ/N(1–11), [Tyr10]OFQ/N(1–11) and [IodoTyr10]OFQ/N(1–11) given supraspinally in mice were antinociceptive in the tailflick assay in mice. The tyrosine analogs showed similar potencies as OFQ/N(1–11) but longer durations of action. This response was readily reversed by the opioid antagonist naloxone despite poor affinities for these analogs at opioid receptors. Another compound, [Tyr11]OFQ/N(1–11) was highly epileptogenic, inducing naloxone-sensitive seizures in greater than 50% of the mice tested at doses comparable to those examined with the other analogs. These results indicate that it is possible to make analgesic OFQ/N(1–11) analogs. The activity of [IodoTyr10]OFQ/N(l–l 1) suggests that it may prove useful as a radioligand in exploring potential OFQ/N(1–11) binding sites.