Small Molecules are Supposed to Correct Pathological Stress Response
Max Planck scientists design chemical compounds for future drugs for treatment of anxiety disorders and depression
Stress can make people ill, especially, if the organism`s molecular machinery isn`t capable to cope with it. Numerous studies in patients have identified the protein molecule FKBP (FK506 binding protein) 51 as a sensitive regulator of stress response. FKBP51 determines the signal transmission efficiency of the stress hormone cortisol in the organism and thus provides an ideal approach for therapeutic intervention in case of sickness.
Scientists around Florian Holsboer, Director of the Max Planck Institute of Psychiatry, have for the first time succeeded in developing small chemical substances which affect the molecular function of FKBP51. In doing so, they paved the way for designing new pharmacological targets for the whole substance class of the FKB proteins in order to develop future drugs, not only in the field of stress regulation.
Although treatment of anxiety disorders and depression with antidepressants is usually successful, it is, nevertheless, not satisfactory as it is partly only after months that any therapeutic effects can be noticed. The observation that patients with certain polimorphisms in the FKBP51 coding gene recuperate more quickly after treatment with antidepressants makes this protein a particularly attractive possible medical target. Felix Hausch, Research Group Leader at the Max Planck Institute of Psychiatry, therefore investigates how the biological function of FKBP51 can be influenced by interaction with smaller substances in order to normalize thereby the control of the organism`s actual stress response.
Figure legend: Model of the spatial nuclear contacts of the binding area of FKBP51 with the newly developed chemical substance 20. (FKBP51 is shown as a purple cloud structure with shadowed contact areas to the coloured ligand 20.)
Due to its capacity to inhibit the glucocorticoid receptor, FKBP51 plays a very important role in the stress reaction of the body. This receptor then reacts accordingly less insensitive to the stress hormone cortisol which, in turn, causes a weaker adaptation to stress. Important for this interaction with the glucocorticoid receptor is an enzymatically active pocket of FKPB51 (Figure). This reactive area of FKBP51 can be blocked by binding of the natural substance FK506. For the very first time, Felix Hausch and his colleages developed on the structural basis of FK506 low molecular chemical compounds which alter the activity of FKBP51.
„We are optimistic that the FKBP ligands designed by us will influence the biological function of FKBP51“, Felix Hausch says. „Now, studies involving animal experiments will have to show if those ligands are also effective in correcting an elevated stress reaction in the organism. In this case, we would have developed the basic chemical component for future drugs which would help the patients much more directly and, hopefully, also more rapidly than current antidepressants.“
Ranganath Gopalakrishnan, Christian Kozany, Steffen Gaali, Christoph Kress, Bastiaan Hoogeland, Andreas Bracher, Felix Hausch
Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52
Journal of Medicinal Chemistry, March 29, 2012, DOI: 10.1021/jm201746x
Ranganath Gopalakrishnan, Christian Kozany, Yansong Wang, Sabine Schneider, Bastiaan Hoogeland, Andreas Bracher, Felix Hausch
Exploration of Pipecolate Sulfonamides as Binders of the FK506-Binding Proteins 51 and 52
Journal of Medicinal Chemistry, March 29, 2012, DOI: 10.1021/jm201747c
For further information please contact:
Dr. Barbara Meyer
Max Planck Institute of Psychiatry, Munich
Phone: +49 89 30622-616
Fax: +49 89 30622-348
Date of press release: 30.03.2012