The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.
The opioid receptor pharmacology of GSK1521498 compared to other ligands with differential effects on compulsive reward-related behaviours.
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DOI：
10.1007/s00213-014-3666-3
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发表时间：
2015-01
影响因子：
3.4
通讯作者：
Henderson, Graeme
中科院分区：
文献类型：
--
作者：
Kelly, Eamonn;Mundell, Stuart J.;Sava, Anna;Roth, Adelheid L.;Felici, Antonio;Maltby, Kay;Nathan, Pradeep J.;Bullmore, Edward T.;Henderson, Graeme
新型阿片受体拮抗剂 GSK1421498 已被证明可以减轻动物和人类的奖励驱动的强迫行为，例如寻求兴奋剂药物或暴饮暴食。在这里，我们报告了 GSK121498 受体药理学的新数据，与纳曲酮、纳洛酮、6-β-纳曲醇和纳美芬进行了比较。确定新型阿片拮抗剂 GSK1521498 是否是 μ 阿片受体 (MOPr) 的正构拮抗剂或变构拮抗剂，以及它是否具有中性拮抗剂或反向激动剂特性。采用放射性配体结合测定和[35S]GTPγS结合测定的组合。 GSK1521498完全取代了[3H]纳洛酮与MOPr的结合，并且没有改变[3H]纳洛酮从MOPr观察中解离的速率，与其与MOPr上的正位点的结合相一致。当MOPr过表达时，GSK1521498表现出反向激动作用，但当MOPr表达水平低时则不表现出反向激动作用。在高受体表达密度条件下的平行研究中，纳洛酮、纳曲酮、6-β-纳曲醇和纳美芬表现出部分激动作用，而不是先前报道的纳洛酮和纳曲酮的反向激动作用。在接受长时间吗啡预处理的小鼠脑组织中，GSK1521498 表现出轻微的反向激动作用。 GSK1521498 和纳曲酮对强迫性奖励寻求的影响之间的差异可以说与 GSK1521498 更具选择性和完全的 MOPr 拮抗作用相对于纳曲酮的部分 MOPr 激动作用有关。 GSK1521498 的药理学差异还在于其在高水平 MOPr 表达下的反向激动剂功效，但这可能不太可能有助于病理生理表达水平的行为分化。
The novel opioid receptor antagonist, GSK1421498, has been shown to attenuate reward-driven compulsive behaviours, such as stimulant drug seeking or binge eating, in animals and humans. Here, we report new data on the receptor pharmacology of GSK121498, in comparison to naltrexone, naloxone, 6-β-naltrexol and nalmefene. To determine whether the novel opioid antagonist, GSK1521498, is an orthosteric or allosteric antagonist at the μ opioid receptor (MOPr) and whether it has neutral antagonist or inverse agonist properties. A combination of radioligand binding assays and [35S]GTPγS binding assays was employed. GSK1521498 completely displaced [3H]naloxone binding to MOPr and did not alter the rate of [3H]naloxone dissociation from MOPr observations compatible with it binding to the orthosteric site on MOPr. GSK1521498 exhibited inverse agonism when MOPr was overexpressed but not when the level of MOPr expression was low. In parallel studies under conditions of high receptor expression density, naloxone, naltrexone, 6-β-naltrexol and nalmefene exhibited partial agonism, not inverse agonism as has been reported previously for naloxone and naltrexone. In brain tissue from mice receiving a prolonged morphine pre-treatment, GSK1521498 exhibited slight inverse agonism. Differences between GSK1521498 and naltrexone in their effects on compulsive reward seeking are arguably linked to the more selective and complete MOPr antagonism of GSK1521498 versus the partial MOPr agonism of naltrexone. GSK1521498 is also pharmacologically differentiated by its inverse agonist efficacy at high levels of MOPr expression, but this may be less likely to contribute to behavioural differentiation at patho-physiological levels of expression.
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影响因子：
64.8
作者：
Ango, F;Prézeau, L;Fagni, L
通讯作者：
Fagni, L
DOI：
10.1124/jpet.111.180943
发表时间：
2011-10-01
影响因子：
3.5
作者：
Ignar, Diane M.;Goetz, Aaron S.;Hommel, Jonathan D.
通讯作者：
Hommel, Jonathan D.
DOI：
10.1186/1471-2210-3-14
发表时间：
2003-12-01
期刊：
BMC Pharmacology
影响因子：
--
作者：
Brillet, Karl;Kieffer, Brigitte L.;Massotte, Dominique
通讯作者：
Massotte, Dominique
DOI：
10.1073/pnas.1300393110
发表时间：
2013-06-25
影响因子：
11.1
作者：
Burford, Neil T.;Clark, Mary J.;Alt, Andrew
通讯作者：
Alt, Andrew
影响因子：
7.3
作者：
Bagley, EE;Chieng, BCH;Connor, M
通讯作者：
Connor, M