Abstract by Emil Märcher-Rørsted

For decades serotonin 2A receptor agonism has been considered an undesirable off-target effect in potential drug candidates. Natural and synthetic compounds possessing activity at this receptor have been relegated to the category of recreational drugs however, recent research has supplied ample support for the re-evaluation of these compounds as putative therapeutics for central nervous system disorders in combination with psychotherapy. This recent development has resulted in a heightened academic and commercial interest in classic serotonin 2A agonists, otherwise known as psychedelics and an increasing necessity to understand the underlying mode of action governing the remarkable effects of these compounds. This thesis describes the exploration and extension of several structural motifs, all of which pertain to one of three classic chemotypes in serotonin 2A agonists, the phenethylamines. Specifically, the importance of the 2,5-dimethoxy substitution pattern was investigated, showing that removal of the 2’ or 5’ position methoxy group was highly detrimental to in vivo potency, but not in vitro potency and binding affinity. The synthesis and application of selective serotonin 2A agonist tool compound 25CN-NBOH was revisited, resulting in a safer and more effective procedure for the procurement of this compound. Finally, the conformational restriction of 25CN-NBOH as its 1,6-disubstituted piperidine analogs were synthesized and characterized in vitro. This characterisation showed that only a single bioactive enantiomer of 4-((6-(2-hydroxyphenyl)piperidin-2-yl)methyl)-2,5-dimethoxybenzonitrile exists and this discovery serves as the grounds for new hypotheses on the binding conformation of 25CN-NBOH.