NOVEL OPIOID RECEPTOR (MOR) ANALGESICS
The invention describes novel analogues of 14-methoxymetopon (14-MM), a μ opioid receptor (MOR) ligand with a unique pharmacological profile, for the treatment of moderate-to-severe acute and chronic pain
Pain is a constant backdrop to daily life and a disabling symptom of many medical conditions, pain control is one of the most important therapeutic priorities. Opioid analgesics are the cornerstone drugs for the treatment of moderate-to-severe acute and chronic pain. Unfortunately opioid analgesics have a number of severe side effects such as respiratory depression, nausea, sedation, dizziness or constipation. With continued administration, opioids show variable degrees of tolerance, physical dependence and abuse potential. These facts limit the clinical usefulness of traditional opioids. It is clearly of paramount importance to opioid drug development to address these issues. 14-Methoxymetopon (14-MM) is considerably more active than morphine in producing analgesia in different pain models, but causes much less pronounced side effects in terms of physical dependence, addiction potential and development of tolerance in rodents. 14-MM does not induce respiratory depression, evokes significantly less hypotension and bradycardia, and produces minimal sedation compared to sufentanil in dogs. 14-MM produces much reduced constipation than morphine in mice. These earlier findings prompted us to synthesize novel analogues of 14-MM.
A number of new opioid agonists have been synthe-sized, analytically characterized and pharmacologically evaluated in vitro in opioid receptor binding and functional assays and in vivo for analgesic activity. Several compounds exhibited high affinity in the subnanomolar range and selectivity for the mu opioid recetor (MOR) in comparison to the kappa (KOR) and delta receptor (DOR), while they were high efficacy agonists. The new ligands showed high antinociceptive potency in pain tests in mice, while they – unlike morphine and 14-MM - produced no significant motor dysfunction in the mouse rotarod test. The new compounds also exhibited less behavioral changes in the Irwin-Screen observation test in mice in comparison to the reference compounds morphine and 14-MM.
- the new class of 14-MM analogues is synthetically readily accessible
- the new MOR agonists have considerably higher antinociceptive potency than the reference compound morphine
- favorable side effect profile in comparison to morphine and 14-MM
Stichwortemorphinans, analgesics, pain therapeutics,