Development and in Vitro Characterization of a Novel Bifunctional μ-Agonist/δ-Antagonist Opioid Tetrapeptide

Medical School and College of Pharmacy, Department of Pharmacology, University of Michigan, Ann Arbor 48109, USA.
ACS Chemical Biology (Impact Factor: 5.33). 09/2011; 6(12):1375-81. DOI: 10.1021/cb200263q
Source: PubMed


The development of tolerance to and dependence on opioid analgesics greatly reduces their long-term usefulness. Previous studies have demonstrated that co-administration of a μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist can decrease MOR agonist-induced tolerance and dependence development after chronic exposure. Clinically, a single ligand displaying multiple efficacies (e.g., MOR agonism concurrently with DOR antagonism) would be of increased value over two drugs administered simultaneously. Guided by modeling of receptor-ligand complexes we have developed a series of potent non-selective opioid tetrapeptides that have differing efficacy at MOR and DOR. In particular, our lead peptide (KSK-103) binds with equal affinity to MOR and DOR but acts as a MOR agonist with similar efficacy but greater potency than morphine and a DOR antagonist in cellular assays measuring both G protein stimulation and adenylyl cyclase inhibition.

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Available from: Irina D Pogozheva
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    • "When µ and δOR agonists are combined, the inhibition of GI transit is greater than a µOR agonist alone in a rodent model of GI inflammation (Pol et al., 1994). However, we are not aware of pharmacological experiments combining δOR antagonists with µOR agonists on GI transit specifically, although recent evidence suggests that this combination has potential analgesic advantages over morphine (Dietis et al., 2009; Mosberg et al., 2011). Therefore, we tested whether blockade of δOR modulates the inhibitory effects of µOR agonists on the GI tract. "
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