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Development of new therapeutic substances and strategies for treatment of pain in patients with advanced stages of cancer

Final Report Summary - NORMOLIFE (Development of new therapeutic substances and strategies for treatment of pain in patients with advanced stages of cancer)

The applications of oral (morphine) pills or transdermal patches with lipophylic 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 extend that pain treatment is reduced by the doctor or refused by the patients.

The discoveries of the last years indicated the changes in expressions of pro- and antynociceptive receptors in pathologically changed peripheral tissues as well as in central nervous system. The modulation of these receptors with composition of receptor ligands may block nociceptive signal formation and transmission more effectively than traditional monotherapies.

The objectives of this project have been focused on development of new multi-target antinociceptive compounds that may interact with peripheral receptors expressed in inflamed and/or pathologically modified tissues and suppress generation and transmission of nociceptive signals from the periphery to CNS. Compounds partial penetration into the central nervous system and interaction with receptor systems involved in nociceptive signal transmission and pain perception should result in synergic periphery / CNS pain suppression. Compounds have been especially developed for the prospective treatment of pain of terminal / metastatic cancer.

The project involved, in general, complementary scientific objectives: chemistry, in vitro biopharmacology and in vivo pharmacology that were accomplished by multidisciplinary integrated teams. Syntheses of new compounds, designed by theoretical (SAR) analysis, have been accomplished in chemical laboratories. Over a hundred new compounds have been designed and synthesised during the first stages of the project.

These compounds activities have been evaluated in in vitro tests of receptor binding to opioid receptors and in in vitro functional cellular tests. The results allowed the project to select compounds for in vivo tests in animals, utilising a specially developed model of metastatic cancer pain. The final in vivo studies were performed with the compounds developed using large scale syntheses.

The accomplishment of the project resulted in a new type of compounds that have been proposed as a new generation of analgesics, especially designed for treatment of various chronic pains, particularly pain of patients with advanced stages of cancer. The designed and synthesised molecules have been further tested in biological and pharmacological in vitro and in vivo tests to select the most promising molecules.

To obtain the most accurate answer, standard tests have been performed and especially modified as well as new tests developed and tested. The data allowed to select several molecules that will be promoted for further development as a medicines.

Individual partners of the project have already started promoting activities of their own compounds for further studies and / or seek for involvement of industry in further development of this type of analgesics.

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