Constipation is the most frequently encountered side effect in the chronic use of opiates to treat cancer pain and in the maintenance of opiate addicts. An opiate antagonist with only peripheral activity, when co- administered with the opiate would prevent or substantially reduce constipation. Standard opiate antagonists as their quarternary salts have been evaluated in the clinic and have shown undesirable effects.
The aim of this application is to identify a peripheral antagonist from among a group of 14-amino-N-cyclopropylmethyldihydronormorphinone derivatives, which will limit access to the central nervous system. The proposal is based on the discovery that 14-acetamidomorphinone is approximately 1000 times more potent as a morphine antagonist in the mouse warm water tail withdraw test when administered centrally than peripherally. The synthesized candidates will be similarly screened and the best will be evaluated in two tests of peripheral activity in mice, i.e., prevention of morphine's inhibition of gastrointestinal motility and reversal of loperamide's antinociceptive activity in the mouse writhing assay. If successful, a Phase II application will be made for detailed pharmacology and toxicology in animals. At that stage it would be hoped that a partnership with a pharmaceutical company could be formed to complete the development.
The market for cancer pain treatment runs into hundreds of millions of dollars every year as a large number of people suffer from this disease. Opioids are used for this pain treatment and as a result constipation is the most frequently encountered side effect. An opiate when co-administered with an antagonist with selective peripheral activity, would prevent or substantially reduce constipation, Thus the market share for an agent, as proposed will be substantial.
