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

倍半萜和倍半萜类化合物(SQT)是一类重要的天然物质，存在于各种精油、水果和蔬菜中。在我们最近的合作项目中，我们从五种选定的植物中鉴定和量化了SQT，并表征了它们在人体内的代谢和吸收。此外，这些分离的物质与激动剂GABA急性短期共同作用后，被用于研究它们在人GABAA受体上的调节变构潜力。GABAA受体是中枢神经系统中最重要的抑制性受体，在抗松弛、抗惊厥和镇静方面是重要的药物靶点。我们的研究证明了一些SQT在不同的受体亚型上都有可能成为有效的变构调节剂，无论是负性的还是正性的。此外，我们发现正调制器的二进制组合令人惊讶地根本没有正调制。此外，我们可以证明，在消化过程中被认为是在体内建立的虎杖烯和石竹烯的衍生物SQT是一种亲脂结构，能够与磷脂双层内的GABAA受体的跨膜片段结合，并直接作用于受体蛋白。另一种选择是它们穿透细胞膜，通过结合受体的胞内域或与受体的胞内结合伙伴来调节受体的功能。然而，这种调节活动需要更长时间的SQT存在。其他SQT的细胞内调节也被显示出来，提示在抑制性神经传递过程中不同的分子通路的调节。在这个项目中，我们的目标是验证这一假说，并从选定的SQT在不同GABAA受体上的长期影响中破译短期效应。此外，基于我们到目前为止所获得的见解，我们的目标是有目的地衍生化SQT，并随后评估它们对不同GABAA受体亚型的调节潜力。通过这些实验，我们的目标是促进对SQTS对GABAA受体调控的了解。

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.