Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain.
Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain.
复制标题
DOI：
10.1213/ane.0b013e3181e0cdaf
复制
发表时间：
2010-07
影响因子：
5.7
通讯作者：
Naguib M
中科院分区：
文献类型：
--
作者：
Xu JJ;Diaz P;Astruc-Diaz F;Craig S;Munoz E;Naguib M
大麻素受体2 （CB2）激动剂最近作为神经性疼痛治疗的潜在治疗靶点而受到关注。在这项研究中，我们表征了一种新型化合物N ' -[(3Z)-1-（1-己基）-2-氧-1,2-二氢- 3h -吲哚-3-乙基]苯并肼（MDA19）的药理学特征，这是一种CB2激动剂。我们对人和大鼠CB1和CB2受体进行了放射配体结合试验和多次体外功能试验。在大鼠和CB2+/+和CB2 - / -小鼠的各种神经性疼痛模型中，评估了MDA19在逆转神经性疼痛中的作用。MDA19对人CB2的亲和力是人CB1受体的4倍（Ki = 43.3±10.3 vs 162.4±7.6 nM），对大鼠CB2的亲和力是大鼠CB1受体的近70倍（Ki = 16.3±2.1 vs 1130±574 nM）。在鸟苷三磷酸(GTP)γ[35S]功能试验中，MDA19在人CB1和CB2受体以及大鼠CB1受体上表现为激动剂，但在大鼠CB2受体上表现为逆激动剂。在3 ',5 ' -环腺苷单磷酸（cAMP）实验中，MDA19对大鼠CB1受体表现为激动剂，而对大鼠CB2受体没有表现出功能活性。在细胞外信号调节激酶1和2激活试验中，MDA19在大鼠CB2受体上表现为激动剂。MDA19在大鼠和CB2+/+小鼠中以剂量相关的方式减轻脊神经结扎或紫杉醇引起的触觉异常性痛，但在CB2 - / -小鼠中没有，表明CB2受体介导了MDA19的作用。MDA19不影响大鼠运动活动。我们发现MDA19在体外对大鼠CB2受体表现出独特的功能特征，并且在体内表现为CB1/CB2激动剂，具有蛋白质激动剂的特征。MDA19有可能减轻神经性疼痛，而不会对中枢神经系统产生不良影响。
Cannabinoid receptor 2 (CB2) agonists have recently gained attention as potential therapeutic targets in the management of neuropathic pain. In this study, we characterized the pharmacological profile of the novel compound N′-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]benzohydrazide (MDA19), a CB2 agonist. We used radioligand binding assays and multiple in vitro functional assays at human and rat CB1 and CB2 receptors. The effects of MDA19 in reversing neuropathic pain were assessed in various neuropathic pain models in rats and in CB2+/+ and CB2−/− mice. MDA19 displayed 4-fold-higher affinity at the human CB2 than at the human CB1 receptor (Ki = 43.3 ± 10.3 vs 162.4 ± 7.6 nM) and nearly 70-fold-higher affinity at the rat CB2 than at the rat CB1 receptor (Ki = 16.3 ± 2.1 vs 1130 ± 574 nM). In guanosine triphosphate (GTP)γ[35S] functional assays, MDA19 behaved as an agonist at the human CB1 and CB2 receptors and at the rat CB1 receptor but as an inverse agonist at the rat CB2 receptor. In 3′,5′-cyclic adenosine monophosphate (cAMP) assays, MDA19 behaved as an agonist at the rat CB1 receptor and exhibited no functional activity at the rat CB2 receptor. In extracellular signal-regulated kinases 1 and 2 activation assays, MDA19 behaved as an agonist at the rat CB2 receptor. MDA19 attenuated tactile allodynia produced by spinal nerve ligation or paclitaxel in a dose-related manner in rats and CB2+/+ mice but not in CB2−/− mice, indicating that CB2 receptors mediated the effects of MDA19. MDA19 did not affect rat locomotor activity. We found that MDA19 exhibited a distinctive in vitro functional profile at rat CB2 receptors and behaved as a CB1/CB2 agonist in vivo, characteristics of a protean agonist. MDA19 has potential for alleviating neuropathic pain without producing adverse effects in the central nervous system.