Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
Center for Advanced Pain Studies, Department of Neuroscience, University of Texas at Dallas, Richardson, TX 75080, USA.
Mar Drugs. 2023 Feb 2;21(2):110. doi: 10.3390/md21020110.
Marine cyanobacteria are a rich source of bio-active metabolites that have been utilized as leads for drug discovery and pharmacological tools for basic science research. Here, we describe the re-isolation of a well-known metabolite, barbamide, from Curaçao on three different occasions and the characterization of barbamide's biological interactions with targets of the mammalian nervous system. Barbamide was originally discovered as a molluscicidal agent from a filamentous marine cyanobacterium. In our hands, we found little evidence of toxicity against mammalian cell cultures. However, barbamide showed several affinities when screened for binding affinity for a panel of 45 receptors and transporters known to be involved in nociception and sensory neuron activity. We found high levels of binding affinity for the dopamine transporter, the kappa opioid receptor, and the sigma receptors (sigma-1 and sigma-2 also known as transmembrane protein 97; TMEM97). We tested barbamide in vitro in isolated sensory neurons from female mice to explore its functional impact on calcium flux in these cells. Barbamide by itself had no observable impact on calcium flux. However, barbamide enhanced the effect of the TRPV1 agonist capsaicin and enhanced store-operated calcium entry (SOCE) responses after depletion of intracellular calcium. Overall, these results demonstrate the biological potential of barbamide at sensory neurons with implications for future drug development projects surrounding this molecule.
海洋蓝藻是生物活性代谢物的丰富来源，这些代谢物已被用作药物发现的先导化合物和基础科学研究的药理学工具。在这里，我们描述了在三个不同场合从库拉索岛重新分离出一种众所周知的代谢物——巴豆酰胺，以及巴豆酰胺与哺乳动物神经系统靶标相互作用的生物学特征。巴豆酰胺最初是从一种丝状海洋蓝藻中发现的一种具有杀软体动物活性的化合物。在我们的实验中，我们几乎没有发现巴豆酰胺对哺乳动物细胞培养物具有毒性的证据。然而，当我们筛选一组 45 种已知与痛觉和感觉神经元活性有关的受体和转运体时，发现巴豆酰胺具有多种亲和力。我们发现巴豆酰胺对多巴胺转运体、κ 阿片受体和 sigma 受体（sigma-1 和 sigma-2 也称为跨膜蛋白 97；TMEM97）具有很高的结合亲和力。我们在雌性小鼠分离的感觉神经元中进行了体外实验，以探讨巴豆酰胺对这些细胞钙流的功能影响。巴豆酰胺本身对钙流没有明显影响。然而，巴豆酰胺增强了 TRPV1 激动剂辣椒素的作用，并增强了细胞内钙耗竭后的钙库操纵性钙内流（SOCE）反应。总的来说，这些结果表明巴豆酰胺在感觉神经元上具有生物学潜力，这对围绕该分子的未来药物开发项目具有重要意义。
