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首页> 外文期刊>Life sciences >Pharmacological characterization of AR-M1000390 at human delta opioid receptors.
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Pharmacological characterization of AR-M1000390 at human delta opioid receptors.

机译：AR-M1000390对人三角洲阿片受体的药理学表征。

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摘要

We investigated the pharmacological properties of a newly synthesised delta agonist AR-M1000390, derived from SNC-80 ((+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N -diethyl-benzamide), in the neuroblastoma cell line SK-N-BE expressing only human delta-opioid receptors. Binding and functional experiments showed a weak affinity (K(i) = 106 +/- 34 nM) correlated with a weak potency (EC(50) = 111 +/- 31 nM) to inhibit the forskolin-stimulated cAMP accumulation. Sustained activation of opioid receptors in the presence of the maximal inhibitory concentration of AR-M1000390 produced a rapid and strong desensitization. In order to examine the contribution of internalization and down-regulation in the desensitization processes, binding and functional experiments were conducted in the presence or in the absence of hypertonic sucrose solution to block clathrin-dependent opioid receptor endocytosis. We observed both the inability of AR-M1000390 to down-regulate opioid receptors and the absence of any effect of sucrose on desensitization. The lack of delta-opioid receptor internalization by AR-M1000390 was further corroborated by confocal microscopy using antibodies directed either against the endogenous delta-opioid receptors or the FLAG-tagged delta-opioid receptors stably expressed in the SK-N-BE cells. These data suggest that uncoupling rather than internalization is responsible for delta-opioid receptors desensitization by AR-M1000390.
机译：我们研究了SNC-80（（+）-4-[（αR）-alpha-（（（2S，5R）-4-allyl-2,5-在成神经细胞瘤细胞系SK-N-BE中仅表达人δ-阿片受体的二甲基-1-哌嗪基）-3-甲氧基苄基] -N，N-二乙基-苯甲酰胺。结合和功能实验表明，弱亲和力（K（i）= 106 +/- 34 nM）与弱势（EC（50）= 111 +/- 31 nM）相关，以抑制毛喉素刺激的cAMP积累。在最大抑制浓度的AR-M1000390存在下，阿片样物质受体的持续活化产生了快速而强烈的脱敏作用。为了检查内在化和下调在脱敏过程中的贡献，在高渗蔗糖溶液存在或不存在下进行结合和功能实验，以阻断网格蛋白依赖性阿片受体内吞作用。我们既观察到AR-M1000390无法下调阿片受体，又观察到蔗糖对脱敏没有任何作用。通过共聚焦显微镜，使用针对内源性δ-阿片受体或在SK-N-BE细胞中稳定表达的带有FLAG标签的δ-阿片受体的抗体，通过共聚焦显微镜进一步证实了AR-M1000390缺乏δ-阿片受体的内在化。这些数据表明，解偶联而非内在化是AR-M1000390引起的阿片类受体脱敏的原因。

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