The development of long-acting opioid antagonists which selectively form divalent bonds with opioid receptors will be continued. Naltrexone,a potent narcotic antagonist, will be modified at the C-6 position with reactive groups. The groups will be attached to the 6 alpha or 6 beta position and varied in length in an effort to obtain ligands which possess maximum selectivity and efficiency in the covalent binding to opioid receptors. Oxymorphone, a potent agonist that is closely related to naltrexone, will be converted to target compound containing C-6 substituents that are identical to those in the antagonist series. All target compounds will be tested for agonist and antagonist effects in mice, guinea pig ileum, and rat-brain tissue. The narcotic antagonists will also be elaluated for their ability to inhibit opiate dependence in mice. Protection studies will be carried out to determine the specificity of the effects in vivo and in vitro. The antagonist and agonist target compounds that are most selective will be prepared in radiolabeled form for inital sudies directed toward the characterization of opioid receptors.