SAFER: Selective serotonin 5-HT2A receptor agonists towards safer drugs

Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter that combines the effects of regulation of mood, appetite, and sleep, with effects on cognitive functions, like memory and learning. The serotonergic system is very complex, comprising 14 different receptor subtypes: 13 G protein-coupled receptors (GPCRs) and one ligand-gated ion channel. The SAFER project has a particular focus on the 5-HT2A receptor subtype, which is a validated drug target in the treatment of schizophrenia and other psychoses, cluster headaches, and glaucoma.
Accumulating clinical evidence suggests that 5-HT2A receptor agonists can relieve the suffering of treatment resistant depressive patients and anxiety in terminal ill cancer patients. However, their therapeutic mode of action is currently poorly understood due to low selectivity of available drugs. Furthermore, the impact of selectively on the activation of different signaling pathways of the 5-HT2A receptor is unknown, suggesting that there is an urgent need for identifying new functionally selective ligands.
Recent developments in GPCR pharmacology have shown that agonists can exhibit functional selectivity by preferentially triggering alternative intracellular signaling pathways. The SAFER project will exploit this mechanism to identify functionally
Selective Agonists For the 5-HT2A sErotonin Receptor. Combining the knowledge accumulated at the University of Copenhagen about the development of ligands for the 5-HT2A receptor, GPCR pharmacology, molecular modeling and database development, with Examine’s extensive chemistry know-how and SARomics Biostructures’ structural biology platform, SAFER is well positioned to address this important scientific and societal challenge.

The SAFER project will train five PhD students in pharmacology, chemistry, crystallography, computational drug design and scientific database development. The consortium members include University of Copenhagen (Denmark), SARomics Biostructures (Sweden) and
Enamine (Ukraine).