Summary of the project:
Prolonging the life expectation of patients with advanced cancer could be done by modern medicine. However, progressive pain that is associated with progression of the disease is the major factor that destructs the last moments of life. Severe progressive and uncontrolled pain is a major reason of requesting euthanasia. The applications of oral (morphine) pills or transdermal patches with lipophilic analgesic drugs are the most common treatments of cancer pain. These compounds penetrating into central nervous system produce side effects (respiratory depression, constipation, tolerance, sedation, etc) to such extent that pain treatment is reduced by doctors or refused by the patients. The discoveries of the last years indicated the changes in expressions of pro- and antinociceptive receptors in pathologically changed peripheral tissues as well as in the central nervous system. The concerted modulation of these receptors in combination with designed receptor ligands may block nociceptive signal formation and transmission more effectively than traditional monotherapies. The objective of this project is to focus on the development of new multitarget compounds and methods which will interact with opioid receptors expressed in inflamed and/or pathologically modified tissues. Partial penetration into the central nervous system will result in synergistic pain suppression via interaction between the peripheral and central nervous system. Alternatively, newly developed compounds could be applied directly into central nervous system to interact with the specific, pathological set of receptors. The developed compounds will be screened in vitro in a cell silicon hybrid biosensor and selected compounds, in vivo in rodent's cancer pain models. The project will yield new basic data on structural requirements of analgesics for treatment of persistent cancer pain in advanced stages and will develop new compounds characterized to the stage that will allow promoting them for further clinical phase testing.