Experimental structure-activity relationship (SAR) studies of salvinorin A, a unique non-nitrogenous opioid receptor ligand, have recently identified analogs with varying degrees of kappa (k), mu (?) and delta (d) opioid receptor affinity. Mixed k and ? agonists appear to be useful in the treatment of stimulant abuse. Mu-selective agonists based on salvinorin A appear to show promise as lead compounds for the development of analgesics with a reduced tendency for tolerance and dependence. To date, the laboratories of Thomas Prisinzano (University of Iowa) and Richard Rothman (NIDA) have synthesized and tested over 50 salvinorin A analogs with varying degrees of selectivity for the k opioid receptor (KOR) versus the ? opioid receptor (MOR). These SAR data have been provided to the Venanzi group for modeling of the molecular properties which determine optimal KOR and MOR binding affinity and selectivity. The long-range goal is to identify the chemical features that can be """"""""tuned"""""""" to produce a ligand with specified KOR/MOR selectivity. The work will be carried out in an iterative fashion in which the present SAR data lead to preliminary statistical models, which in turn will be refined as additional SAR data become available. Standard ligand-based modeling techniques, such as Comparative Molecular Field Analysis and Comparative Molecular Similarity Analysis, will be used to identify regions of salvinorin A where changes in steric bulk or electrostatic properties, for example, may to lead to analogs with improved binding affinity and/or selectivity. This work will be complemented by quantum mechanical studies of selected analogs in order to gain additional insight into how their molecular structure and properties, such as keto-enol tautomeric equilibria, may be related to trends in binding affinity. Certain analogs of salvinorin A that bind to k opioid receptor (KOR) proteins appear to have promise in the modulation of the abuse-related effects of central nervous system stimulants, such as cocaine. Other analogs of salvinorin A that bind to ? opioid receptors (MORs) appear to be useful in the development of analgesics with low potential for tolerance and dependence. The principal investigator, in collaboration with researchers who synthesize the analogs and test their pharmacological activity, will use computer modeling techniques to design analogs with specific KOR/MOR selectivity in order to identify compounds that may be useful in the treatment of drug abuse and/or act as safe analgesics. ? ? ?