The aims of the application are in accord with the mission of the Medications Development Division of NIDA to provide new treatments for substance abuse. The principal aim of the project is to provide potential pharmacotherapies for opiate dependence with profiles similar to buprenorphine, but having higher mu opioid receptor efficacy. These compounds would combine the best characteristics of buprenorphine and methadone, in effect providing a safer (than methadone) high efficacy treatment. The target ligands are based on 14-(O)-ethers and -esters of the opioid antagonist naltrexone and on the orvinols. We have established a structural relationship between these series based on molecular modeling studies and similarities in their pharmacological profiles. Certain 14-(O)-ethers of naltrexone have been shown to have unexpectedly high mu opioid receptor (MOR) agonist potency in vivo along with a long duration of action. This activity can now be explained by their relationship to the orvinols. It is proposed to re-synthesize and further evaluate the lead compound and to evaluate other ethers and related esters of naltrexone to produce drug candidates which will have the desirable properties of good acute safety and long duration of action. Control of MOR efficacy will primarily be achieved through modification of the 14-(O)-side chain, a strategy we have used previously in closely related series. The orvinols provide an opportunity to target compounds that access the same regions of space as the naltrexone derivatives and are predicted to display similar pharmacological profiles. Control of MOR efficacy will be through modification of the C7 side chain. The orvinols are a series of compounds that we have considerable experience working with, buprenorphine being a notable representative of this family. [unreadable] [unreadable] [unreadable]