Sesquiterpenes und sesquiterpenoid derivatives in food aromas: physiological derivatives and structure-activity relationships in the modulation of GABAA and glycine receptors

食品香料中的倍半萜烯和倍半萜衍生物：GABAA 和甘氨酸受体调节中的生理衍生物和构效关系

• 批准号: 314348207
• 负责人: Professorin Dr. Andrea Büttner
• 金额: --
• 依托单位: Institut für Klinische Neurobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/314348207?language=en
• 关键词: Sesquiterpenes; und; sesquiterpenoid; derivatives; food

Sesquiterpenes and sesquiterpenoids (SQTs) are an important naturally occurring substance class, present in various essential oils, fruits and vegetables. In our recent collaborative project, we have identified and quantified SQTs from five selected plants and characterized their metabolization and uptake into the human body. Moreover, the isolated substances were used for studies on their modulatory allosteric potential at human GABAA receptors following acute short co-application together with the agonist GABA.GABAA receptors are the most important inhibitory receptors in the central nervous system and are important drug targets in terms of antirelaxation, anticonvulsion and sedation. Our research demonstrated the potential of some SQTs to be potent allosteric modulators, both negative and positive, on different receptor subtypes. Furthermore, we found out that binary combinations of positive modulators surprisingly showed no positive modulation at all. Additionally, we could show that humulol and caryolanol, which are derivatives of humulene and caryophyllene assumed to be built in vivo during digestive processes, seem to have a more pronounced modulatory effect at the GABAA receptor than their parent compounds, indicating that digestive processes might also generate neurotropic activity. SQTs are lipophilic structures which are able to bind to the transmembrane segments of GABAA receptors within the phospholipid bilayer and act directly at the receptor protein. Another option is that they permeate the cellular membrane and modulate the function of the receptor by binding at its intracellular domain or to intracellular binding partners of the receptor. However, such modulatory activity requires longer presence of SQTs. Intracellular modulations have been shown for other SQTs, suggesting modulation of different molecular pathways during inhibitory neurotransmission. In this project we aim to test this hypothesis and decipher short-term from long-term effects of selected SQTs at various GABAA receptors. Moreover, based on our insights obtained so far, we aim for a purposeful derivatization of SQTs and subsequent assessment of their modulatory potential on different GABAA receptor subtypes. With these experiments, we aim to advance the knowledge of the GABAA receptor modulation by SQTs.

倍半萜烯和倍半萜类化合物 (SQT) 是一种重要的天然物质，存在于各种精油、水果和蔬菜中。在我们最近的合作项目中，我们识别并量化了五种选定植物的 SQT，并表征了它们的代谢和人体吸收。此外，分离的物质还用于研究其与激动剂GABA急性短期联合应用后对人GABAA受体的调节变构潜力。GABAA受体是中枢神经系统中最重要的抑制性受体，是抗松弛、抗惊厥和镇静方面的重要药物靶点。我们的研究证明了一些 SQT 具有成为不同受体亚型的有效变构调节剂（负向和正向）的潜力。此外，我们发现正调节剂的二元组合令人惊讶地根本没有表现出正调节。此外，我们还可以证明，葎草醇和石竹醇（被认为是在消化过程中在体内形成的葎草烯和石竹烯的衍生物）似乎比其母体化合物对 GABAA 受体具有更明显的调节作用，表明消化过程也可能产生神经营养活性。 SQT 是亲脂性结构，能够与磷脂双层内 GABAA 受体的跨膜片段结合，并直接作用于受体蛋白。另一种选择是它们渗透细胞膜并通过结合其胞内结构域或受体的胞内结合配偶体来调节受体的功能。然而，这种调节活性需要 SQT 存在更长时间。其他 SQT 也显示出细胞内调节，表明抑制性神经传递过程中不同分子途径的调节。在这个项目中，我们的目标是测试这一假设，并解读所选 SQT 对各种 GABAA 受体的短期和长期影响。此外，根据我们迄今为止获得的见解，我们的目标是对 SQT 进行有目的的衍生化，并随后评估其对不同 GABAA 受体亚型的调节潜力。通过这些实验，我们的目标是增进对 SQT 调节 GABAA 受体的了解。