Peripheral Narcotic Antagonists--14-Aminomorphinones

Constipation is the most frequently encountered side effect in the chronic use of opiates to treatthe maintenance of opiate addicts. An opiate antagonist with only peripheral activity, when co-adminwould prevent or substantially reduce constipation. Standard opiate antagonists as their quarternaryevaluated in the clinic and have shown undesirable effects. We will identify a peripheral antagonist4-amino-N-cyclopropylmethyldihydronormorphinone derivatives, which will limit access to the centralproposal is based on the discovery that 14-acetamidomorphinone is approximately 1000 times more poteantagonist in the mouse warm water tail withdraw test when administered centrally than peripherally.candidates will be similarly screened and the best will be evaluated in two tests of peripheral actiprevention of morphine's inhibition of gastrointestinal motility and reversal of loperamide's antinomouse writhing assay. If successful, a Phase II application will be made for detailed pharmacology aanimals. At that stage it would be hoped that a partnership with a pharmaceutical company could be fdevelopment.