SYNTHESIS AND EVALUATION OF NOVEL LIGANDS FOR CENTRAL NERVOUS SYSTEM (CNS) RECEPTORS LIDER/015/L-6/14/NCBR/2015
The project is carried out at the Institute of Organic Chemistry and Technology, the Faculty of Chemical Engineering and Technology (WIiTCh), Cracow University of Technology (CUT), in cooperation with the Department of Pharmaceutical Chemistry, Institute of Pharmacology, Polish Academy of Sciences (PAN), and the Faculty of Pharmacy, Collegium Medicum, Jagiellonian University, Cracow.
THE PROJECT IS FINANCED BY:
Depressive disorders, apart from schizophrenia and anxiety disorders, are the most common and the most expensive disorders of the Central Nervous System (CNS) during treatment. According to the estimates of World Health Organisation (WHO), depression will take the second position in the world list of disorders causing premature death in 2020. In the highly developed countries, the costs of treating CNS disorders are growing, which means that these disorders are not only a crucial issue from the point of view of public health and the wellbeing of a society, but also create a great economic concern.
One of the biggest obstacles for the current pharmacotherapy is the fact that the drugs used in treating CNS disorders achieve their full effect after a few weeks of application and their effectiveness is often reduced by developing tolerance. Moreover, it is estimated that ca. 30% of patients are treatment resistant.
The aim of the project
The most important physiological functions, which are influenced by serotonin, are emotional states, sleep, memory, sexual behaviours, pain, and also blood circulation and heartbeat. Moreover, it is well known that serotonin influences the occurrence of pathological processes, such as schizophrenia, depression, anxiety, or sleeping disorders. The diversity of functions fulfilled by serotonin can be explained by the fact that the serotonin receptors are connected with other neurotransmitter systems.
The serotonin receptors can be divided into 7 different classes (5-HT1 – 5-HT7) and 15 subtypes on the basis of their structural properties and functioning. Even though in the course of the last 50 years a tremendous progress has been made in defining the receptor structure and in attempting to assign functions to particular receptors, it is still a great challenge for the researchers to define precisely the role of the 5-HT receptors which would explain the rich diversity of this group.
Many authors show that the strategy of finding new medicines in the group of compounds influencing serotonergic system yields high likelihood to obtain effective antidepressants.
It is known nowadays that many neurotransmitter systems are responsible for physiological dysfunctions in relation to the behaviour and mood. However, the 5-HT1A receptors fulfill the key role, which are crucial in pathogenesis and treatment of depression and anxiety. The research conducted in recent years has proven also that given the observed increased density of 5-HT7 receptors in limbic structure of CNS, it is suspected that these receptors have to be taken into account in the context of the occurrence of affective disorders. Numerous findings in the literature prove that the active ligands of 5-HT7 receptors can play a crucial therapeutic role in treating depression and insomnia. The implementation of 5-HT7 receptors in sleep regulation has been proven, and by that it has been demonstrated that the shortening of the REM sleep phase influences the elimination of depressive states. In recent years, it has been suggested in the literature that the receptors 5-HT6 also play a significant role in the case of schizophrenia, depression, and anxiety, and the most recent reports show very promising results of research that support the therapeutic potential in treating the Alzheimer disease.
Taking into consideration the above mentioned points, the aim of the planned research project is the synthesis of the new long-chain ligands of serotonin receptors 5-HT (5-HT1A, 5-HT6, 5-HT7) from the arylpiperazine group (LCAPs). The assessment of ligand activity will be tested with in vitro and in vivo research. The bioactive conformation will be also defined for the most active connections.
In the project it is expected to achieve ligands in an innovative, solvent-free method of synthesis that will be a part of green chemistry.
The research began according to schedule in April 2016. At the first stage of the research, a series of syntheses was conducted, whose aim was to develop a new method of ligand synthesis in microwave radiation (MW) conditions. At the next stage, preliminary assumptions for the method of achieving ligands in MW presence were developed. The universality of this method was assessed in the synthesis of several chosen ligands.
During the work within the molecular modelling, homology models of several serotonin receptors were prepared.
Currently, the syntheses are performed, whose aim is to achieve the first group of ligands of the 5-HT receptors.
The preliminary research results were presented during the 6th RSC/SCI symposium on GPCRs in Medicinal Chemistry, The Aptuit Center for Drug Discovery & Development in Verona, Italy, and during the 2nd Central European Biomedical Congress (CEBC) in Kraków, Poland. The research results were also presented in September during the VII Conversatory on Medicinal Chemistry in Lublin and IV National Nanotechnology and Polymer Congress in San José, Costa Rica.
In October, during the 10th International Warsaw Invention Show (IWIS), presented the results of our studies on the development of a new method for obtaining long chain aryl piperazines (LCAPs) under microwave radiation. This solution was appreciated by the jury and honored with a Special Prize of the Polish Chamber of Chemical Industry in the 5th World Competition of Chemical Inventions, organized by the International Federation of Inventors’ Associations (IFIA) and the Association of Polish Inventors and Rationalizers.
About the project in the media
1. Program MANIA NAUKI Radiofonia 100,5 FM
2. Polska Agencja Prasowa: Scientists from Cracow University of Technology are working on new drugs for depression
3. LoveKrakow.pl: Scientists from CUT are working on new drugs for depression
4. Radio RMF, Rmf24.pl: New drugs for depression? Researchers from the Cracow University of Technology are working on them
5. PolskieRadio.pl: Scientists from Cracow University of Technology are working on new drugs for depression
6. Wyborcza.pl: Scientists from Cracow University of Technology are working on new drugs for depression
7. Radio Kraków: Scientists from Cracow University of Technology are working on new drugs for depression
8. Krakow.TVP.pl: Scientists from Cracow University of Technology are working on new drugs for depression
9. KRKNews.pl: Scientists from Cracow University of Technology are working on the drug for depression. "Promising results"
10. Fitmagazyn.pl: A new way to fight depression
11. Rynekaptek.pl: Krakow: Scientists are working on new antidepressants
12. PulsBiznesu.pl, PB.pl: Researchers are working on new drugs for depression
13. Zdrowie.dziennik.pl: Poles researchers are developing a drug for depression. It can also help with schizophrenia and Alzheimer's
14. RynekZdrowia.pl: Krakow: University of Technology scientists are working on new drugs for depression
15. mpolska24.pl: New drugs for depression? Researchers from the Cracow University of Technology are working on them
16. Infonews.pl: New drugs for depression? Researchers from the Cracow University of Technology are working on them
17. Polskie Radio Kraków z 25 lutego, audycja Pracują na Nobla: Cracow University of Technology is working on drugs for depression
18. Radio Eska: At the University of Technology are working on a drug for depression!
19. Dziennik Polski They are working on new drugs for depression
20. MEDYCYNA PRAKTYCZNA PSYCHIATRIA
At Cracow University of Technology work on new antidepressants
- Jolanta Jaśkowska, PhD Eng – Project manager
- Damian Kułaga, M.Eng.
- Anna K. Drabczyk, M.Eng.
- Magdalena Malinowska, M.Eng
- Grzegorz Satała, M.Sc.
- Łukasz Szeleszczuk, Pharm.D
- Paweł Śliwa, PhD Eng.
- Bożena Tyliszczak, PhD Eng.
- Przemysław Zaręba, M.Eng.
Jolanta Jaśkowska, PhD Eng – Project manager
Research and didactic assistant professor at the Institute of Organic Chemistry and Technology, WIiTCh, CUT. In her scientific work, she conducts research whose aim is to discover new bioactive compounds, particularly ligands of serotonin receptors. Moreover, she develops methods of synthesis in solvent-free conditions as a part of “green chemistry”. Jolanta has both theoretical and practical knowledge of managing research projects. Apart from participating in scientific projects, she has led six projects in cooperation with companies in pharmaceutical, cosmetic, and food industry. She is a co-author of two international patent applications and one granted patent. She has a documented knowledge of commercialising scientific research, which she has gained during numerous trainings organised by technology transfer centres, agencies for enterprise development or by the Foundation for Polish Science. Moreover, Jolanta has completed post-graduate studies of Scientific Research and Development Manager at the University of Economics and Innovation, Lublin, Poland. Her knowledge of commercialisation was also broadened during the internship at Stanford University, California; within the MNiSW (Ministry of Science and Higher Education) programme Top 500 Innovators. The aim of the programme was to give unique competences to participants, allowing them to lead innovative research that is aimed at the needs of the recipients and with the goal of introducing the product of the research to the market.
Anna K. Drabczyk, M. Eng
Graduate in 1st and 2nd cycle studies at WIiTCh, CUT. Her research work related to the engineer and master theses was realised at the Institute of Organic Chemistry and Technology. She has gained experience in organic synthesis, and in particular in synthesis of ligands of 5-HT from long chain derivatives of arylpiperazines (Long Chain Arylpiperazines, LCAPs) in the presence of microwave radiation. She can independently interpret data necessary for affirmation of structures of the acquired IR, 1HNMR, UV-Vis, and UPLC-MS connections. Apart from the technical experience acquired at the Cracow University of Technology, she has the experience gained during internships in the pharmaceutical industry.
Damian Kułaga, M.Eng
Graduate in Chemical Technology at WIiTCh, CUT. Damian has a broad experience in organic synthesis and analytics, which he gained during studies and internship at Zakłady Azotowe Tarnów Mościce and Chemiczno-Farmaceutyczna Spółdzielnia Pracy “ESPEFA” (Chemical and Pharmaceutical Cooperative). Since 2013, he has been employed as a Synthesis Specialist in Selvita S.A. company. He has acquired necessary skills for planning and leading organic syntheses. He has experience in performing reactions: Suzuki, Ulmann, Buchwald, HWE, alkylation, amination, amidation, reduction, oxidation, hydrogenation, hydrogenolysis, ozonolysis, cyclisation, protection i deprotection, cyaniding, and many others. Moreover, Damian has gained experience in conducting processes in anaerobic conditions, strictly anhydrous, and in low temperatures: both on a small scale for screening research (several milligrams), medium (several grams) and large scale for process optimisation (tens and hundreds grams). He specialises in the synthesis of heterocyclic, steroid, and aromatic compounds. He has an excellent knowledge of techniques for purification of raw products via column chromatography and its various types, including p-TLC, maceration, and crystallisation. Moreover, he has gained experience in confirmation of compound structure on the basis of IR, HNMR, MS, and in the use of databases and programmes like: Reaxys, PASS, SciFinder, MervinSketch, MestReNova, ChemBioDraw, eMolecules.
Magdalena Malinowska, M.Eng
PhD student and lecturer at the Institute of Organic Chemistry and Technology, WIiTCh, CUT. She has a broad experience in the synthesis of active substances and purification of products via preparative liquid chromatography, maceration, or crystallisation. Moreover, she has acquired skills necessary for conducting HPLC analyses as well as developing and validating analytic methods for monitoring reaction progress, and assessing purity of the achieved products. Her work as a junior synthesis specialist at Selvita S.A. company has given her experience in the synthesis of combinatorial libraries of bioactive compounds, optimisation of production processes for discovering the most effective reaction paths and in developing synthetic paths with patent analysis. She also gained knowledge and skills in analytic methods (HPLC, GCMS, IR, UV/VIS) during her work as a self-dependent analyst in Quality Control Department at Teva Operations Poland, Sp. z o.o.
Grzegorz Satała, M. Sc.
Graduate in Biophysics, at the Faculty of Biochemistry, Biophysics and Biotechnology at the Jagiellonian University in Cracow. Gregory is employed as assistant at the Department of Medicinal Chemistry in the Institute of Pharmacology Polish Academy of Sciences, where he has gained experience in drug discovery based on high throughput screening of large compounds libraries by in silico and in vitro methods for structure-activity relationship exploration. His research is focused on designing and searching for new antidepressant and anxiolytic agents. Moreover, he has participated in numerous research projects and industry internships in Poland and other countries. He gained scientific experience, among others, at the Pliva Cracow in Quality Assurance Department and Analytical Research and Development Department.
Łukasz Szeleszczuk, Pharm.D
Graduate in Pharmacy, Medical Substances Design specialisation, at Medical University of Warsaw (WUM). Currently, Łukasz is employed as a research and didactic assistant professor at the Department of Physical Chemistry, Faculty of Pharmacy, WUM. He has gained broad experience in recording and interpreting 1H, 13C, 15N NMR spectra in solid bodies and solutions, as well as in molecular modelling (Gaussian, DMol3, DFTB, VAMP, CASTEP) and drug design (Sybyl, Discovery Studio). He has also acquired a master’s diploma in pharmacy. His knowledge of pharmacy has been broadened by the experience gathered during many internships in Poland and other countries in pharmacies and pharmaceutical companies (Bayer Heath Care, Wuppertal, and Bayer Animal Health, Monheim).
Paweł Śliwa, PhD Eng
Research and didactic assistant at the Institute of Organic Chemistry and Technology, WIiTCh, CUT. His research interests concern molecular modelling of active compounds, especially GPCR receptor protein modelling, and the application of QM/MM hybrid methods in the analysis of GPCR-ligand complexes. Paweł gained scientific experience, among others, at the Institute of Pharmacy, Polish Academy of Sciences. He has gained rich professional experience at management positions in food and pharmaceutical companies. He led the development department and quality control laboratory at Wytwórnia Wódek i Likierów and was the Chief Technologist. As a part of his duties, he led development projects in quality control, including projects co-financed by the European Union. As a Quality Control Systems Specialist at Teva Operations S.A. he created, verified, and approved GMP documentation. He has also managed quality assurance projects and assessed the conformance of the projects with the pharmacy law and GMP principles.
Bożena Tyliszczak, PhD Eng
Research and didactic assistant professor at the Chair of Chemistry and Technology of Polymers, WIiTCh, CUT. She has gained experience in recording and interpreting FT-IR, UV-VIS spectra, DSC analyses, and measuring with scanning electron microscope. Moreover, she has gained knowledge and skills of chemical technology, materials engineering, nanotechnology, as well as she has rich experience in planning research work. She has gained her practical knowledge by leading numerous research projects, during research and industry internships, and by finishing postgraduate studies in Biomaterials – medical materials, at the Faculty of Materials Science and Ceramics, AGH University of Science and Technology, Kraków. She has also gained knowledge and experience in commercialisation during several courses at, among others, Stanford University within the MNiSW (Ministry of Science and Higher Education) programme Top 500 Innovators, and postgraduate studies in Managing research projects and commercialisation at Cracow University of Economy, and in Manager of Scientific Research and Development Work at the University of Economics and Innovation, Lublin.
PhD student and a graduate of first and second cycle studies at WIiTCh, CUT. He has experience in the field of multistep organic synthesis in small and large scale, especially the alkylation reaction in the synthesis of biologically active compounds, as well as in solvent-free reactions and synthesis in the presence of microwave radiation in the “Green chemistry” trend. He also deals with the purification of raw products using crystallization techniques, maceration and adsorption separation techniques, purity assessment (HPLC) and structure confirmation (1H NMR, 13C NMR, IR, UV-Vis, MS) of the obtained compounds. He also has knowledge in the field of molecular modeling using DFT methods and in the support of databases and programs such as: Reaxys, SciFinder, MervinSketch, MestReNova, eMolecules.
LIDER programme at Cracow University of Technology
LIDER PROGRAMME OF THE NATIONAL CENTRE FOR RESEARCH AND DEVELOPMENT is directed at young scientists who want to gather experience in managing a research project and gain competences in independent creation, management, and leading their own research team. The programme also stimulates the cooperation between the scientists and entrepreneurs with conducting research that can be later implemented and commercialised. Moreover, it encourages the mobility between sectors, universities, and research centres.
Tadeusz Kościuszko Cracow University of Technology (CUT) is a public university oriented towards technology with a 70 years’ tradition. It is one of the leading technical universities in Poland. CUT’s mission is to educate scientific staff and highly qualified engineers who can offer solutions to the challenges of national and world economy, ensuring the growth of passion for research and participating in national and global scientific exchange. Moreover, the university has been serving the economy and the society for decades by solving technical and technological problems and implementing research results into business practice.
Currently, CUT educates over 17,000 students at full-time and extramural studies, 1st and 2nd cycles, and PhD and postgraduate studies. CUT offers 25 programmes of studies (1st cycle) at seven faculties. Such wide choice means diversity of intellectual pursuits and solving ambitious tasks with the supervision of highly-qualified staff.
Many of the 1200 members of the scientific and didactic staff are distinguished specialists who participate in inter-university work and international research teams. Thanks to their knowledge and qualifications, our university holds a distinct position in Poland and in the international scientific community.
Faculty of Chemical Engineering and Technology educates students at five programmes of studies: Chemical Technology, Chemical and Process Engineering, Biotechnology, Nanotechnology and Nanomaterials (with the Faculty of Physics, Mathematics and Computer Science), and Construction Chemistry (with the Faculty of Civil Engineering).
The graduates from the Faculty are prepared for the work in technology and engineering, as well as in sciences and research, in the broadly-defined chemical industry.
During the studies, the students learn the basics of organic and inorganic technology, biotechnology, and chemical engineering. They also explore the environmentally friendly, energy and material saving wasteless technologies, technological solutions for lowering the burden of industry on the environment, the technologies related to refinery industry, low-tonnage products, drugs, cosmetic products, household chemicals, crop protection products, materials for electronic industry, and construction chemicals. Moreover, the study the technologies of obtaining polymers, methods of studying their properties, as well as processing and recycling of plastic materials, state-of-the-art solutions for biopolymers and synthesis of nanomaterials and catalysts. The students are taught about biotechnological process engineering, environmental protection, and renewable energy sources. Moreover, they can learn modern methods of physical and physicochemical methods of measurement in chemical analysis.
The Faculty can award the doctor title in the field of technical sciences in chemical technology and engineering disciplines, and in the field of chemical sciences in chemistry discipline.
In the 2011 the Central Committee for Degrees and Titles granted the Faculty of Chemical Engineering and Technology, Cracow University of Technology, the right to award the doctor habilitatus title in the field of technical sciences: chemical technology.
Jolanta Jaśkowska, PhD Eng.
+48 12 6282740