The classic opioid antagonists naloxone and naltrexone possess ketone functional groups at position 6 and act as inverse agonists in the opioid dependent state. Instead of a ketone at position 6, 6b-naltrexol and 6b-naltrexamide contain an alcohol and amide, respectively. These synthetic derivatives function as neutral antagonists in in vitro and in vivo systems previously exposed to morphine, and are under investigation as improved treatments for narcotic dependence. We are currently studying which specific structural characteristics differentiate inverse agonists from neutral antagonists at the mu opioid receptor. Current synthetic efforts are aimed at fully reducing the ketone at position 6 of naltrexone using using modified Wolff-Kishner conditions. The compound obtained after subsequent hydrogenolysis, 17-(cyclopropylmethyl)-(3,14-dihydroxy)-4,5a-epoxymorphinan, will direct us in the design of improved analogs for the treatment of narcotic dependence. In conclusion, our data further support the hypothesis that differences in opioid ligand structure target unique conformations of the mu opioid receptor.
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Back to The 33rd Northeast Regional Meeting (July 14-17, 2005)