Dynorphin A, an endogenous neuropeptide, is has high affinity and selectivity for the kappa opioid receptors. It has been reported that the N-terminus ?message? sequence is important for kappa opioid receptor activation while the ?address? sequence is designated as the potency-enhancing domain responsible for the high specificity of dynorphin A. Two novel lead Dyn A analogues, arodyn (aromatic dynorphin), and JVA-901, have displayed different structure-activity relationships from Dyn A. It is therefore hypothesized that arodyn and JVA-901 bind differently to the kappa opioid receptors. The goal of this research proposal is to identify potent and selective kappa opioid receptor antagonists. To pursue this goal novel selective kappa receptor antagonists will be designed utilizing classic and combinatorial peptide libraries and evaluated using Chinese hamster ovary cells stably expressing opioid receptors. The combination of classical and combinatorial approaches will be used to modify the sequences of the two aforementioned lead peptides and generate focused peptide libraries. Combinatorial peptide libraries offer the advantage of synthesizing a variety of peptides simultaneously and allows the introduction of various combinations of amino acids in the sequence of arodyn and JVA-901. Syntheses will be done using solid phase peptide synthesis. There are many potential clinical applications of kappa agonists and antagonists, including the prevention of pancreatitis, neuroprotection (epilepsy) and anti-convulsants, potential treatment in cocaine abuse and opioid dependence as well as use in pharmacological assays as pharmacological tools to help understand kappa receptor-ligand interactions at the molecular level since kappa-selective peptide antagonists are limited.