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

• Published in: ACS chemical biology Vol. 6; no. 12; pp. 1375 - 1381
• Main Authors: Purington, Lauren C, Sobczyk-Kojiro, Katarzyna, Pogozheva, Irina D, Traynor, John R, Mosberg, Henry I
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16-12-2011
• Subjects: Adenylyl Cyclase Inhibitors; Analgesics, Opioid - pharmacology; Animals; Cell Line; CHO Cells; Cricetinae; Cross-Linking Reagents - pharmacology; Drug Tolerance; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Models, Molecular; Narcotic Antagonists - pharmacology; Oligopeptides - metabolism; Oligopeptides - pharmacology; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Rats; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb200263q

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.