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More Selective Serotonin Receptor Agonists -Computational Design of Tracers for Depression and Alzheimer’s Figure 1: Serotonin Receptor model Figure 2: Agonist inside the receptor binding site Aim: Design serotonin receptor agonists that can be used as tracing molecules to directly visualize and monitor serotonin receptor activity in the human brain in several clinical conditions. Background The serotonergic receptor system has been linked to depression, anxiety, social phobia, schizophrenia, obsessivecompulsive disorder, panic disorder, migraine, hypertension and eating disorders. Serotonin receptors are believed to partly mediate the effects of several antipsychotics and antidepressants. Agonist tracers can be used as tools to study diseases and to develop new drugs. Computer-based agonist ligand design Figure 1, Receptor 3D model: Agonists bind to an active conformation of the receptor structure. Models have been built of serotonin receptors based on homologous crystal structures and validated against already known agonists. Figure 2, Model-based agonist ligand design: The 3D structure model is used to design agonist ligands that can fit inside it. Specifically, the receptor structure is probed for amino acids that are close to the ligand and might bind by for example hydrogen bonds or aromatic-aromatic interaction. Experimental: Ligand synthesis, pharmacological testing and in vivo studies This project is part of a large ongoing national Center for Integrated Molecular Brain Imaging (www.cimbi.org), which has already been running ligand synthesis, pharmacological testing and in vivo studies for four years. This means that results produced in this project has the unique opportunity to be tested experimentally within a very short time frame and lead to a new clinical tool. For more information contact David Gloriam, [email protected] Department of Drug Design and Pharmacology, room 111