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（SQTs）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，我们从五种选定的植物中鉴定和量化了sqt，并表征了它们的代谢和进入人体的吸收。此外，分离的物质被用于研究它们在与激动剂GABA急性短期共应用后对人GABAA受体的调节变构电位。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、镇静等方面是重要的药物靶点。我们的研究表明，在不同的受体亚型上，一些SQTs可能是有效的变构调节剂，无论是阴性的还是阳性的。此外，我们发现正调制器的二元组合令人惊讶地显示根本没有正调制。此外，我们可以证明葎草烯和胡萝卜醇是葎草烯和石竹烯的衍生物，它们被认为是在体内消化过程中形成的，似乎比它们的母体化合物对GABAA受体有更明显的调节作用，这表明消化过程也可能产生嗜神经活性。SQTs是一种亲脂性结构，能够与磷脂双分子层内GABAA受体的跨膜片段结合，直接作用于受体蛋白。另一种选择是，它们渗透细胞膜，并通过结合在其胞内区域或受体的胞内结合伙伴来调节受体的功能。然而，这种调节活性需要更长时间的sqt存在。细胞内调节已显示在其他SQTs中，表明在抑制性神经传递过程中调节不同的分子途径。在本项目中，我们的目标是验证这一假设，并从各种GABAA受体上选择的sqt的长期影响中解读短期影响。此外，基于我们迄今为止获得的见解，我们的目标是有目的地衍生sqt，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，我们的目标是推进对GABAA受体通过SQTs调节的认识。

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.