Description
Growing problem of depression, its fatal epidemiological prognosis and limitations of available pharmacotherapy (side effects profile, partial efficacy) point to the need of searching new antidepressant drugs. The project is a continuation of earlier studies which were organized as Academia-based platform to discover substances with antidepressant potential. The current research is aimed at further development of the Platform activities to find new solutions for the treatment of depressive illnesses. The results obtained within the project may be a basis (in form of knowledge and methodologies) for future effective and innovative medicines. In a longer perspective, it can help in overcoming social and economic problems associated with depression. Relations between the Polish and Norwegian research institutions are based on the exchange of experience and cooperation which result in joint publications and patent application as well as increasing the scientific experience of scientists. Proceeded with success it can be a basis for next grant applications.
Summary of project results
Mental disorders like depression (affecting ~400 million people globally), dementia (~35 million), and schizophrenia, (~21 million) are among the most common causes of disease burden. Because current drugs are characterised by numerous adverse side effects, a delayed onset of action and often lack effect in a significant proportion of patients, the need for new antidepressant drugs is hence high. The PLATFORMex project (
www.platformex.eu) aimed at the development of new compounds of potential psychotropic properties (mainly antidepressant) of different mechanisms of actions, i.e. targeting serotonergic system (5-HT receptors and serotonin transporters, SERT), metabotropic glutamatergic receptors (group III mGluR) and GABAB receptors. The Platform functions on three complementary levels: in silico – constructing of homology models, pharmacophore models, filters for multistep virtual screening (VS), designing new ligands, selecting/prioritizing mVS hits, developing and automating new tools for VS; in vitro – organic synthesis of 5-HTR/SERT ligands and mGluR allosteric modulators and affinity and functional activity screening at the above mentioned molecular targets; in vivo – evaluating pharmacological activity of novel compounds in animal models. The Project resulted in synthesis of novel groups of compounds acting on different receptors: 5-HT6 selective ligands, dual 5-HT6/D2 ligands, selective agonists of 5-HT7 receptor and positive allosteric modulators with agonistic activity of metabotropic glutamate receptor mGluR8. Moreover, novel modulators of GABAB receptor were identified using virtual screening approach. New software for analysis of docking results and structure-based pharmacophore models generation was also developed. The most significant scientific results are a subject of two patent applications. The first describes a series derivatives representing low-basicity scaffold which exhibited high affinity for 5-HT7 receptor together with agonist function and high selectivity over the related central nervous system targets. Preliminary behavioural evaluation revealed their procognitive effects suggesting potential application in cognitive dysfunction in schizophrenia. The second application concerns a group of indole and indazole derivatives as positive allosteric modulators of mGluR8 which showed antipsychotic activity.
Summary of bilateral results
In almost all WPs collaboration was a key factor to achieve assumed goals. In a number of activities individual researches from partnering institutions contacted on a daily basis. Steering Committee meetings organized in partnering institutions, research visits between partners and conference meetings facilitated direct contacts, exchange of information, joint work on specific tasks. Although the Project has formally finished, common research continues and new project application was submitted and others are planned.