Tang Yaliang, Wolk Barbara, Britch Stevie C, Craft Rebecca M, Kendall Debra A
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA.
Department of Psychology, Washington State University, Pullman, WA, 99164, USA.
J Pharmacol Sci. 2021 Apr;145(4):319-326. doi: 10.1016/j.jphs.2020.12.006. Epub 2020 Dec 29.
Cannabinoid receptors are a potential target for anti-inflammatory and pain therapeutics. There are two subtypes, CB and CB, and Δ-tetrahydrocannabinol activates both of them, providing an analgesic effect but also psychoactive side effects. The psychoactive side effects are considered to be caused by activation of CB, but not CB. ABK5 is a CB subtype selective agonist that has a very different structure from known cannabinoid receptor agonists. Here, we report anti-inflammatory effects of ABK5 using the T-cell line Jurkat cells, and antinociceptive effect in an inflammatory pain model in rats. Production of the cytokines IL-2 and TNF-α was measured in stimulated Jurkat cells and MOLT-4 cells, and CXCL12-mediated chemotaxis of Jurkat cells was evaluated by a transwell migration assay. Anti-inflammatory and antinociceptive effects of ABK5 were also evaluated in a hindpaw CFA model in rats. ABK5 significantly decreased production of IL-2 and TNF-α measured as both mRNA and protein levels, and reduced chemotaxis towards CXCL12. It also attenuated edema and increased mechanical threshold in the hindpaw of CFA-treated rats. These results suggest that ABK5 is a good lead compound for the development of potential anti-inflammatory and analgesic agents.
大麻素受体是抗炎和止痛治疗的潜在靶点。有两种亚型，CB1和CB2，Δ-四氢大麻酚可激活这两种亚型，产生镇痛作用，但也有精神活性副作用。精神活性副作用被认为是由CB1的激活引起的，而非CB2。ABK5是一种CB2亚型选择性激动剂，其结构与已知的大麻素受体激动剂非常不同。在此，我们报告了ABK5在T细胞系Jurkat细胞中的抗炎作用，以及在大鼠炎症性疼痛模型中的抗伤害感受作用。在受刺激的Jurkat细胞和MOLT-4细胞中测量细胞因子IL-2和TNF-α的产生，并通过Transwell迁移试验评估Jurkat细胞的CXCL12介导的趋化作用。还在大鼠后爪CFA模型中评估了ABK5的抗炎和抗伤害感受作用。ABK5显著降低了以mRNA和蛋白质水平衡量的IL-2和TNF-α的产生，并降低了对CXCL12的趋化作用。它还减轻了CFA处理大鼠后爪的水肿并提高了机械阈值。这些结果表明，ABK5是开发潜在抗炎和镇痛药物的良好先导化合物。
