Depression has become a major socio-economic burden. This mental disorder affects 5% of the adults and it is a major contributor to long-term disability and disease. It has become clear that first-line antidepressants such as SSRIs, SNRIs, and NRIs are not effective enough; 30% of adults relapse after treatment and patients often need to deal with serious side effects. There is a clear need for better therapeutics. Several studies on psychedelics such as psilocin and LSD have shown promising results by improving synaptic plasticity in rats. However, their therapeutic potential is limited due to their hallucinatory and potentially toxic nature, creating an opportunity for medicinal chemistry to develop effective and non-hallucinogenic psychedelic-inspired antidepressants.

This project aims to synthesise 5-HT2A–selective psilocin analogues that can serve as possible leads for therapeutical use. A virtual library will be constructed based on an established catalytic borrowing hydrogen synthesis strategy. A group of promising psilocin analogues will be selected using docking and molecular dynamics studies, which will be synthesised using a high throughput experimentation workflow. Finally, the obtained compounds will undergo an in vitro and in vivo validation.