The objective of this proposal is to design, synthesize, and characterize the analgesic potential of chemical delivery systems (CDS's) that provide for brain-directed delivery of opioid peptides. Such compounds could significantly improve pain control in critically ill patients, offer more effective treatment for drug addiction and might also be developed for treating several disorders of the central nervous system (CNS) that involve opioid neuropetides. Studies in this proposal use the concept of """"""""molecular packaging"""""""" which was conceived in order to circumvent athe primary obstacles that neuroactive peptides encounter int the circulation before reaching CNS target sites. The hydrophilic peptides must penetrate the blood-brain barrier (BBB) and escape peptidase digestion by numerous brain endothelial enzymes. Molecular packaging disguises neuropeptides with three functional groups (T, L, and S) to deliver intact peptide to brain tissue. In the most important step, an enzymatic reactions """"""""locks- in"""""""" the CDS by quaternization of a redox targetor, T. The bulky, non- toxic, lipophilic L group masks the peptide structure from peptidases while allowing passive transport through brain endothelial cells. Addition of spacer, S, functions modifies the cleavage rate of free peptide from the molecular package to optimize delivery of opioid peptides at CNS target sites. Preliminary studies demonstrated that molecular packaging can improve CNS delivery of neuropeptides. Manipulation of the S function increased the magnitude of the anticataleptic activity measured after systemic administration of CDS's for a tripeptide analog of thyrotropin releasing hormone *TRH). Feasibility studies indicated that the predicted retrometabolic conversions of an encephalon-CDS's can be monitored. A more important result was the improved analgesic activity shown for the packaged encephalon analog. Specific studies in this proposal optimize the delivery concept for opioid peptides and include systematic examination of each functional group. Physical-chemical and metabolic profiles are examined in vitro to confirm property changes predicted on the basis of drug design. Receptor binding and distribution studies examine drug and key metabolite properties. Analgesic activity is evaluated in selected compounds. The pharmacological profile and initial safety profile of the most promising compounds will be examined for therapeutic potential.
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