Synthesis of pyridopyrimidine derivatives and ligands with double bond to 5-HT1AR and SERT

Project Title
Synteza pochodnych pirydopirymidyny ligandów o podwójnej wiązalności do 5-HT1AR oraz SERT.
Financing Institution
prof. dr hab. Franciszek Herold
Project Objective

The aim of the project will be the synthesis and determination of biological activity of new pyrido [1,2-c] pyrimidine derivatives, compounds with double bond to 5-HT1AR and SERT. The results of in vitro and in vivo biological tests will allow the assessment of the impact of the modifications of the structure of compounds on their biological activity. The premise of the research is to obtain a new third-generation antidepressant from the SSRI + or MTA (Multi Target Agents) group. The research on both groups (SSRI +, MTA) is one of the leading directions of medical chemistry research on a new antidepressant, and in the case of research in the MTA group - pioneering research. In order to achieve the aim of the research, the knowledge of the team implementing the project will be used in the field of medical chemistry, physicochemistry, pharmacokinetics, pharmacology and in silico research. The implementation of the project's research objective will be based on the following methodology: - designing ligand structures based on structural analogies with known ligands with binding to 5-HT1AR or SERT, modifications of the leading structures and preliminary results of molecular modeling final relationships; synthesis of final compounds planned in the project in five independent series (synthesis of over 60 new compounds is planned); - preparation of analytical samples for physicochemical and biological tests and evaluation of their purity (HPLC); - confirmation of the chemical structure (by IR, NMR spectroscopy methods) and composition (elemental analysis and HRMS spectrometry), carried out for all final compounds; - in vitro affinity test for 5-HT1AR and SERT using appropriate radioligands (for all final compounds); - in vitro radioreceptor studies in an extended receptor profile (5-HT2A, 5-HT2c, 5-HT6, 5-HT7, α and D2) for ligands showing the highest affinity for one of the 5-HT1AR or SERT molecular targets, - in vivo study functional activity at pre- and postsynaptic 5-HT1A receptors (mousse induced hypothermia test and rat LLR test); - Phase I transition stability study for selected ligands from both series (ADME study); - study of antidepressant activity for compounds showing the highest binding to 5-HT1AR and SERT and having the highest stability in phase I pass (Porsolt test and mobility test); - in silico testing for ligands of both series (molecular docking, SAR); - SAR analysis for all tested compounds; structure optimization based on SAR, ADME and in silico research, which may significantly affect the effective search for the leading structure in research on new SSRI and or MTA antidepressants. The synthesis carried out under the project will contribute to the knowledge of the medical chemistry of heterocyclic compounds showing biological activity. The promising results of previous studies on pyrido [1,2-c] pyrimidine derivatives indicate a high probability of obtaining ligands with high affinity for 5-HT1AR and SERT, which may lead to an effective new third-generation SSRI antidepressant. On the other hand, the planned research on MTA ligands may lead to an antidepressant with a new mechanism of action, a shorter latency period and greater effectiveness in comparison with the second-generation SSRI drugs most frequently used in the pharmacotherapy of depression. The results of biological research envisaged in the project will allow to determine the influence of the ligand structure modifications on binding to 5-HT | AR and SERT, optimization of the leading structure leading to obtaining new compounds with antidepressant activity in the SSRH or MTA group.