This on-going interdisciplinary study of opiate narcotics seeks to identify, characterize and predict molecular determinants and modes of receptor binding which (1) lead to high affinity and selectivity in binding to different classes of receptors and (2) modulate relative efficacy, and hence exent of agonism and antagonism, within a given opiate family. To these ends we plan: A) Extensive structure activity studies of mu/kappa nonpeptide opiates. Theoretical investigation and measurement of receptor binding and efficacy for selected known analogs with varying degrees of mu- and kappa- selectivity to determine molecular indicators of high affinity, selectivity and relative efficacy at these receptors. Similar studies of new series of achiral beta-aminoamides related to the kappa-selective compound U-50,488 could yield new kappa-selective agonist and antagonists; B) Continued studies of opioid peptides and peptidomimetic, conformationall-restricted Tyr-Gly dipeptides to elucidate commonalities between peptides and nonpeptides and identify structural requirements for hgh affinity binding at the mu- or delta-receptor; C) Determination of conformational characteristics of beta endorphin analogs to test the hypothesis that alpha helical segments in the 14-31 region are required for high receptor affinity; D) Expansion of theoretical efforts to include more systematic conformational search strategies, computation of molecular electrostatic potentials, and evaluation of drug interactions with both site-specific and global receptor models; E) Expansion of our experimental efforts to provide better measures of activity with which to compare our theoretical results. These new efforts include: (1) measurement of biochemical consequences of opiate binding, such as stimulation of GTPase activity, (2) use of these results together with measured receptor affinities to determine relative efficacies of selected analogs, 3) a systematic comparison of different protocols for determining in vivo agonist and antagonist activities and 4) investigation of the relationship between efficacy and in vitro and in vivo end points for agonist and antagonist activities. These comprehensive interdisciplinary studies will substantially advance our understanding of the relationship between fundamental molecular properties, modes of receptor binding, receptor affinity and selectivity, efficacy and in vitro and in vivo agonist and antagonist activities of diverse families of opioids.