Basic information
Investigator: RNDr. Tomáš Petrásek Ph.D.
Main recipient: National Institute of Mental Health (NIMH)
Co-recipient: University Hospital Hradec Kralove
Research period: 1/5/2025 – 31/12/2028
Total budget: 11,840,000 CZK
NIMH budget: 7,034,000 CZK
Supported by: Czech Health Research Council (AZV ČR)
Annotation
Schizophrenia is a serious mental disorder, burdening both the patients themselves and the public health system. Currently used antipsychotics successfully alleviate positive symptoms, by primarily targeting type 2 dopamine receptors (D2Rs). However, the treatment is less efficient in most cases against negative and cognitive symptoms, has serious side effects, and up to 20% cases do not sufficiently respond to monotherapy. Therefore, there is a pressing need to develop drugs with enhanced safety and efficacy. The most effective treatment strategy so far is the use of multi-receptor ligands, such as the third-generation antipsychotics. Due to the high expression of type 3 serotonin receptors (5-HT3R) in the key brain regions, 5- HT3Rs represent a promising target for such molecules. Using 5-HT3R antagonists (setrons) as a cotreatment with standard antipsychotics mitigates cognitive and negative symptoms of schizophrenia with reduced side effects. Moreover, setrons have been shown to counteract substance abuse, especially alcohol, which is particularly frequent comorbidity of schizophrenia. Therefore, we hypothesize that dual-action antipsychotics targeting simultaneously 5-HT3R (antagonism) and D2R (partial agonism or antagonism) should be superior to standard therapy, especially in alcohol-dependent schizophrenic patients. In this project, we will develop a family of novel centrally active compounds with dual effect, targeting both 5-HT3R and D2R, characterize their receptor affinities, functional activities, as well as in vivo pharmacokinetics and toxicity. We will test selected candidates in an animal model of psychosis, to assess the efficacy against positive, negative and cognitive symptoms, and also their ability to suppress alcohol intake in a model of alcohol abuse, to identify the most promising lead candidate. Based on pilot data, we believe that our project has a good chance to find a compound which could be patented and pushed towards clinical testing.