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

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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.