The observation that DOR antagonists can mitigate some adverse effects of MOR agonists � such as the development of tolerance and dependence � has motivated several groups to pursue bifunctional MOR agonist/DOR antagonist ligands.  Using structure-based design we have developed several peptide ligands with similar affinity toward MOR and DOR and that function as MOR agonists and DOR antagonists.  Members of this series possess advantages over previously reported examples of MOR agonist/DOR antagonist ligands, but, like most peptides these analogs poorly penetrate the blood brain barrier.  Consequently, our focus has turned to improving the bioavailability of these bifunctional ligands using two complementary approaches: 1. Modifying our lead MOR agonist/DOR antagonist peptides to improve membrane penetration, while preserving their pharmacological profile and 2. Transferring the key pharmacophore elements of these peptides to more drug-like peptidomimetic scaffolds.  Successes, failures, and observations from these parallel approaches toward the development of opioid analgesics with reduced tolerance and dependence liability will be described. Supported by NIDA grant DA003910 and Fellowship support from NIDA Training Grants DA007281 (JPA) and DA007267 (LY).

Development of bifunctional mu opioid receptor (MOR) agonist/delta opioid receptor (DOR) antagonist peptides and peptidomimetics

248th National Meeting (2014)

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