首页> 美国卫生研究院文献>The Journal of Pharmacology and Experimental Therapeutics >Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/μ-Opioid Receptor Ligands: Implications for Therapeutic Applications
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Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/μ-Opioid Receptor Ligands: Implications for Therapeutic Applications

机译:新型双功能伤害感受器受体/μ阿片受体配体的抗伤害感受和抗奖励作用的比较:对治疗应用的启示

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摘要

The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the μ-opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphine-induced CPP. 1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one) (SR14150), a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced analgesia that was naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate morphine-induced CPP. 3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, and partial agonist activity at MOPr, was also a potent analgesic and produced CPP alone, but also modestly attenuated morphine CPP. 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our results suggest that NOPr full-agonist activity is required to modulate opioid-induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a nonaddicting analgesic. The opioid-modulating effects of the NOPr ligands may be used effectively to produce better medications for treatment of drug abuse and pain.
机译:阿片受体家族的成员Nociceptin受体(NOPr)是治疗疼痛和药物滥用的靶标。 Nociceptin / orphanin FQ(N / OFQ)是NOPr的内源性肽,不仅调节阿片类药物的抗伤害感受,而且还阻断了吗啡,可卡因和安非他明等几种滥用药物的奖励作用。我们假设NOPr激动剂在μ阿片受体(MOPr)上具有双功能活性,可能起非成瘾镇痛药或药物滥用药物的作用。在急性热镇痛分析中评估了在MOPr上具有不同选择性和功效的双功能小分子NOPr激动剂,以及它们诱导条件性位置偏爱(CPP)的能力及其对吗啡诱导的CPP的影响。 1-(1-环辛基哌啶-4-基)-吲哚-2-酮(SR14150)是一种高亲和力的NOPr部分激动剂,具有低MOPr亲和力和药效,可产生纳洛酮可逆的镇痛作用。 SR14150既不单独诱导CPP,也不减弱吗啡诱导的CPP。 3-乙基-1-(1-(4-(异丙基环己基)哌啶-4-基)-吲哚-2-酮(SR16507),对NOPr和MOPr都具有高亲和力,对NOPr具有完全的激动剂活性,并且具有部分激动剂活性在MOPr上,它也是一种有效的止痛药,仅产生CPP,但也略微减弱了吗啡CPP。 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one(SR16835),NOPr全激动剂,低亲和性MOPr部分激动剂,不是抗伤害感受性的,不单独产生CPP,而是减弱的吗啡CPP。我们的研究结果表明,需要NOPr全激动剂活性来调节阿片样物质诱导的奖赏,而双功能NOPr / MOPr部分激动剂谱可能适合作为非依赖性镇痛药。 NOPr配体的阿片样物质调节作用可以有效地用于生产用于治疗药物滥用和疼痛的更好的药物。

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