Activities of mixed NOP and μ-opioid receptor ligands
Activities of mixed NOP and μ-opioid receptor ligands
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DOI：
10.1038/sj.bjp.0707598
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发表时间：
2008-02-01
影响因子：
7.3
通讯作者：
Zaveri, N. T.
中科院分区：
文献类型：
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作者：
Spagnolo, B.;Calo, G.;Zaveri, N. T.
背景和目的：同时激活 NOP 和 mu-阿片受体的化合物可能可用作镇痛药和药物滥用药物。进行研究是为了更好地了解此类化合物的生物活性。实验方法：在转染 NOP 和阿片受体的细胞膜上测定结合亲和力。通过 [S-35] GTP gamma S 与细胞膜的结合，并使用体外小鼠输精管制剂和体内甩尾抗伤害测定来确定功能活性。 主要结果：化合物的亲和力范围从对 NOP 受体选择性为 20 倍的 SR14150 到对 mu-阿片受体选择性为 50 倍的丁丙诺啡。在[S-35] GTP gamma S测定中，SR化合物的范围从NOP受体的完全激动剂到拮抗剂，并且大多数是mu-阿片受体的部分激动剂。丁丙诺啡是 mu-阿片受体的低效部分激动剂，但不会通过 NOP 刺激 [S-35] GTP gamma S 结合。在小鼠输精管中，除 SR16430 之外的每种化合物均抑制电诱导的收缩。在每种情况下，除了 N/OFQ 本身之外，抑制作用是由于 mu-阿片受体激活所致，正如 NOP 受体敲除组织中的等效结果所确定的。 SR14150 在甩尾试验中显示出抗伤害活性，而阿片类拮抗剂纳洛酮可逆转该活性。结论和意义：与 mu-阿片受体和 NOP 受体结合的化合物具有抗伤害活性，但每种受体的相对贡献尚不清楚。这些实验有助于表征与两种受体结合的化合物，更好地了解其生物活性背后的机制，并确定新的药理学工具来表征 NOP 和阿片受体。
Background and purpose: Compounds that activate both NOP and mu-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds.Experimental approach: Binding affinities were determined on membranes from cells transfected with NOP and opioid receptors. Functional activity was determined by [S-35] GTP gamma S binding on cell membranes and using the mouse vas deferens preparation in vitro and the tail flick antinociception assay in vivo.Key results: Compounds ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for mu-opioid receptors. In the [S-35] GTP gamma S assay, SR compounds ranged from full agonist to antagonist at NOP receptors and most were partial agonists at mu-opioid receptors. Buprenorphine was a low efficacy partial agonist at mu-opioid receptors, but did not stimulate [S-35] GTP gamma S binding through NOP. In the mouse vas deferens, each compound, except for SR16430, inhibited electrically induced contractions. In each case, except for N/OFQ itself, the inhibition was due to mu-opioid receptor activation, as determined by equivalent results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone.Conclusions and implications: Compounds that bind to both mu-opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These experiments help characterize compounds that bind to both receptors, to better understand the mechanism behind their biological activities, and identify new pharmacological tools to characterize NOP and opioid receptors.