The long-term goals of this research are to design, synthesize and evaluate the biological and conformational properties of peptide or peptidomimetic ligands that are highly potent agonists and delta (and kappa) and delta subtype opioid receptors which can cross membrane barriers. In addition, we will design and synthesize ligands that are highly potent and selective for the mu-deltacomplex opioid receptor and mu opioid receptor complexes. These ligands when used alone or in combinations will be used to examine new modalities for analgesia with little or no addiction potential or other undesirable side effects, and to provide new approaches for the treatment of addiction and for withdrawal. The specific aims to reach these goals include: 1. Using computer assisted drug design methods and biophysical methods to design, synthesize and conformationally evaluate peptide ligands for delta opioid receptor subtypes including the mu-deltacomplex that will be highly efficacious for in vivo analgesia. 2. To use computer assisted methods to design novel ligands related to DPDPE and the deltorphins that interact specifically at the delta1 and delta2 opioid receptors and that will cross the blood brain barrier and other membranes more effectively. 3. To use similar methods as in 2. To design novel analogues of (D- Tca1)CTAP and biphalin that will enable them to more readily cross membrane barriers, especially the blood-brain barrier. 4. Develop systematic approaches to modifying peptides such that they will more readily cross the blood brain barrier. 5. To design analogues with unique biological profiles that can more readily cross the blood brain barrier but that are biotransformed to a more potent and efficacious form. 7. To collaborate with biological colleagues to investigate analogues with ability to be biotransformed to a more active form, that are stable to enzyme degradation, that remain in circulation, etc. 8. To use molecular modeling to design peptidomimetic structures that are more bioavailable but are based on peptide templates.