Design, synthesis and pharmacological evaluation of highly potent analgesics showing less side effects

With 14-methoxymetopon we have found a novel, highly potent analgesic which has, besides its high potency, the advantage of the development of only minimal physical dependence and tolerance and of considerably less pronounced side effects than morphine. The fact that 14-methoxymetopon possesses higher analgesic potency than fentanyl, which is being used in neurolept analgesia, it is feasible that this compound could also be used in neurolept analgesia, especially since it does not show any respiratory depression. The problem of fentanyl and other narcotics used in neurolept analgesia is the life threatening respiratory depression after surgery. To our knowledge, 14-methoxymetopon is the most favourable highly potent analgesic so far described. An important contribution to drug safety and adequate treatment of severe pain could be accomplished with this compound and analogues of it. It is planned to design and synthesize novel analogues of 14-methoxymetopon and to evaluate these substances in different biological and pharmacological tests. We have evidence that modifications of the alkoxy group in position 14 could produce very promising candidates. Thus, among other changes to the 14-metoxymetopon molecule (e.g. alterations of substituents at the nitrogen and in position 5), we plan to prepare further analogues with modifications in position 14. The design of the new molecular structures will be supported by the use of "Computer Aided Drug Design". Delta-Opioid receptor agonists have analgesic properties but induce weaker physical dependence and show a less constipating effect than morphine. In a series of indolo- and benzofuranomorphinans having a methyl substituent at the morphinan nitrogen we found some highly potent delta-selective opioid agonists. With "Computer Aided Drug Design" we want to improve the molecular structures of our delta-agonists concerning delta-opioid receptor affinity and selectivity and prepare these molecules by chemical synthesis. Delta-Opioid receptor antagonists prevent the development of morphine tolerance and dependence. A partial agonist exhibiting mu-agonism and delta-antagonism could be of great value in the development of novel analgesics with less side effects. We have already found such a compound in the indolomorphinan series and plan to introduce certain substitutents at the morphinan nitrogen (e.g. 2-phenylethyl, cyclobutylmethyl) in this class of compounds to get higher mu-agonist and delta-antagonist potency. All new compounds will be tested biologically and pharmacologically for receptor affinity and selectivity, analgesic potency and side effects.

Novel highly potent analgesics with considerable less pronounced side effects have been developed. With 14-methoxymetopon we had found earlier a highly potent analgesic which has, besides the high potency, the advantage of the development of only minimal physical dependence and tolerance and of less pronounced side effects (e.g. respiratory depression) than morphine. In order to further improve the 14-methoxymetopon molecule concerning drug safety (including less pronounced side effects such as physical dependence, tolerance, constipation, respiratory depression etc.), we planned to design and synthesize novel analogues of 14- methoxymetopon and to evaluate these substances in different biological and pharmacological tests. Computer aided drug design was used to optimize the molecule. During the course of the work on this project we succeeded to further improve the pharmacological effects of 14-methoxymetopon by special structural changes. The newly developed compounds exhibit considerably enhanced analgesic potency (up to 400-fold compared to14- methoxymetopon and up to 10,000-fold compared to morphine). The constipative effect, which is a very serious side effect of all strong analgesics in use (e.g. morphine), was dramatically decreased. Respiratory depression was found to be much less pronounced compared to morphine. It was further found that the novel compounds unfold their high analgesic potency also after oral administration. Therefore they could be used in tablets, which makes the administration of drugs much more convenient for patients and physicians. Due do the high lipophilicity of the new compounds, a transdermal application is also feasible. All these aspect should increase patient compliance. This discovery opens up an entirely new approach to exceptionally potent analgesics with very mild side effects. A part of these very promising and encouraging results was used as a basis for the successful development and progress of an EU-project of the 5th framework programme. Due to the highly promising results of both projects, it is planned to found a start-up company in Austria. This company is intended to be a research-based biotech company, committed to the development of new-generation therapeutics for the treatment of chronic pain and rheumatoid arthritis. It aims to improve human health, patient satisfaction, and the quality of life, as well as to reduce the overall costs of healthcare.