How are new drugs designed?

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Scientific research conducted at the Department of Medicinal Chemistry of the Faculty of Pharmacy (Jagiellonian University Medical College) focuses on the search for new biologically active substances acting on the central nervous system (CNS). They may be employed in the therapy of mental and neurodegenerative diseases, in the treatment of epilepsy, in eliminating various types of pain, and in supporting the fight against obesity.

The activity of each drug usually results from the interaction of its molecule with an appropriate "spot" within the body, called the receptor. By binding to receptors, drugs stimulate or inhibit the relevant biochemical reactions in the cells of living organisms. These result in processes that may be used in disorders of tissue and organ function, leading to the "repair" of incorrectly functioning cells. These processes, referred to as therapeutic effect, may manifest themselves, for example, in: increasing or decreasing heart rate, blocking the pain response, limiting the feeling of fear or correcting a depressive mood.

Promising molecules

One of many biologically active substances existing in the central nervous system is serotonin (5-hydroxytryptamine: 5-HT), a neurotransmitter whose receptors participate in numerous processes as important as memory, mood, fear or appetite. It has been proven that new biologically active compounds that inhibit one sub-type of serotonin receptors (5-HT6) may eventually turn out to be more beneficial drugs in the therapy of mental disorders (in comparison with currently used products).

In connection with the research on the function of serotonin in the central nervous system, scientists from the Department of Medicinal Chemistry developed a program called "5-HT6 Plus Platform". Research carried out within this program takes into account the possibility to combine the inhibition of the 5-HT6 receptor with other biological targets that are important for the functioning of particular areas of the human brain. This main research area is carried out in close cooperation between research units of the Jagiellonian University and the Institute of Psychiatry and Neurology in Warsaw, with the Polish pharmaceutical company Adamed. The objective of the project is to develop a new, original psychotropic drug that might be used particularly in such mental disorders as schizophrenia, psychosis and depression.

In the course of neurodegenerative diseases, numerous mental illnesses and disorders of the function of the central nervous system, patients suffer from problems with memory and orientation, difficulties in recognizing their relatives or friends and the lack of proper evaluation of everyday life. The therapy of these disorders, referred to as cognitive disorders, employs drugs that decrease the function of 5-HT6 receptors in the CNS. These drugs, manifesting various influences on several areas of the brain, may have a beneficial effect on other symptoms, including those connected with behavior and psychological functions.

Behavioral disorders and psychological problems that accompany dementia and occur simultaneously are defined as Behavioral and Psychological Symptoms of Dementia (BPSD). They occur in the course of Alzheimer's disease, in psychosis, depression, aggression, in fear and apathy attacks, and they are a significant burden for patients and their caregivers. The assortment of drugs used in such cases includes psychotropic drugs, whose application is the result of observation of their effects in individual patients. On the other hand, there are no drugs that would specifically limit BPSD. Psychotropic drugs used to reduce these symptoms are administered in those disorders beyond the scope of their basic therapeutic indications. Thus, they are formally not permitted for use in dementia and, moreover, their efficacy in this type of disorders is limited and they cause numerous adverse effects in various organs, mainly the cardio-vascular system.

Within the conducted research, several thousand new substances were designed and obtained from which "promising" ones were selected – so-called lead molecules which have a strong anti-psychotic and anti-depressant effect, while not impairing memory (cognitive functions), behavior and psyche (behavioral and psychological functions). This kind of activity profile clearly distinguishes the newly obtained biologically active compounds from currently used drugs. The methods of obtaining and the biological properties of these substances have been described in five international patent applications. Currently, within research grants subsidized by the National Science Centre (NSC), works are developed on substances that may block certain enzymes, including phosphodiesterases in the central nervous system. Additionally, the Department of Medicinal Chemistry is carrying out research with the objective of searching for new, more effective antiepileptic drugs, with particular focus on so-called drug-resistant epilepsy, which cannot be cured with currently known drugs.


From the design to in vivo tests

"Along with the design and synthesis of potentially biologically active chemical compounds, fundamental research is being carried out with the objective of improving the process of searching for new drugs. This process employs computer- aided structure design of new ligands (biologically active molecules) and the design of new computer models of interactions between receptors and ligands as well as the improvement of existing ones. These works resulted in the creation of reliable, new homology models of several types of receptors that are essential for the functions of the central nervous system, such as 5-HT6, 5-HT7, D1 and D2," explains Professor Maciej Pawłowski, who is supervising the research.

The objective of the research related to pharmaceutical chemistry is as follows: at the first stage to design a molecule which promises proper direction of pharmacological activity and at the second stage to synthesize the designed, potentially biologically active compounds intended for initial screening tests. This screening constitutes stage three and is conducted with the use of in vitro methods, based on cell cultures or tissue fragments containing, for example, adequately prepared receptors. New, active chemical compounds selected as a result of such research undergo in vivo tests (i.e., tests on living organisms) on laboratory animals. The results of such tests make it possible to determine the profile of the pharmacological activity of the new substances.

The role of incident and impressive discoveries

One of the elements of research conducted at the Department of Medicinal Chemistry is the synthesis of new compounds of a peptide structure (protein fragments) and their analogues. For this purpose, modern synthesis techniques are employed, on solid phases, constituting a kind of a special polymer matrix on which one of the reagents (participant of a chemical reaction) is "anchored" using a so-called linker, so that later a peptide molecule is created by adding one amino acid after another. The linker plays an important role in these processes. Its properties determine not only the directions of synthesis, the purity and homogeneity of the obtained products, but also the final efficiency of the whole process, which often consists of many stages.

In the course of research conducted at the Department of Medicinal Chemistry on the synthesis of amino acid derivatives on solid phase, it turned out that the fragment used as a linker bound to polymer has unique chemical properties that may be used in numerous chemical processes essential in the search for new drugs. Wide possibilities offered by the application of this fragment are a spectacular discovery referred to as the concept of the pipecolic linker.

The pipecolic linker has become a new tool for solid phase synthesis. The "anchor" discovered in this way makes it possible to synthesize many substances which have very different chemical structure, from the group of peptides, peptidemimetics and smallmolecule organic compounds. This research is carried out in close co-operation with the teams from the Institute of Bioparticles of Max Mousseron (IBMM) in Montpellier and the Institute of Pharmacology of the Polish Academy of Sciences in Kraków. The invention is subject to international patent protection. Works on the potential commercialization of these results are in progress.

Research team: Professor Maciej Pawłowski; Jolanta Obniska, PhD; Paweł Zajdel, PhD; Hanna Byrtus, PhD; Grażyna Chłoń-Rzepa, PhD; Marcin Kołaczkowski, PhD; Anna Czopek, PhD; Monika Marcinkowska, PhD; Krzysztof Kamiński, PhD; Agnieszka Zagórska, PhD; Paweł Żmudzki, PhD; Adam Bucki, MSc; Katarzyna Grychowska, MSc; Vittorio Canale, MSc; Andrzej Miodoński