Opioid analgesics (such as morphine and codeine) are the most powerful analgesics and are the mainstay treatments of acute pain due to cancer and other serious disorders. As powerful pain relievers they can cause serious drug-dependence—leading to substance abuse, in addition to side effects such as nausea, constipation and drowsiness. To overcome the limitations of these narcotic analgesics, Dr. Aldrich's laboratory at KU has designed and developed various novel opioid analogs (Dynorphin A derivatives). The attractive features of these novel compounds are that they produce a similar pain relieving action as morphine, without the addiction liability and substance-abuse potential. Further, these drug molecules were designed to retain their structural similarity to the endogenous compound, Dynorphin A, thus minimizing potential toxic effects.

In order for these novel molecules to be useful as drugs, they have to exhibit certain “drug-like properties,” such as adequate stability when injected into the blood, rapid transfer from blood to the brain, and desirable stability in the brain to exert its pain relieving effect. Using various non-animal models, we have studied these attributes of the compounds. Our results show that these modified Dynorphin A derivatives exhibit rapid transfer into the target organ (brain) and improved stability in the blood compared to Dynorphin A. The important metabolites of the lead Dynorphin A analog in the brain tissue was also determined. Strategic modifications in the structure of Dynorphin A significantly enhance its transport properties and stability in target tissue. These studies provide improved understanding of the structural features essential for the clinical development of these novel compounds.