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Transcript
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, david.gloriam@sund.ku.dk
Department of Drug Design and Pharmacology, room 111