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Development and in vitro characterization of a novel bifunctional ?-agonist/?-antagonist opioid tetrapeptide.


ABSTRACT: 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 ?-opioid receptor (MOR) agonist and ?-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.

SUBMITTER: Purington LC 

PROVIDER: S-EPMC3241856 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Development and in vitro characterization of a novel bifunctional μ-agonist/δ-antagonist opioid tetrapeptide.

Purington Lauren C LC   Sobczyk-Kojiro Katarzyna K   Pogozheva Irina D ID   Traynor John R JR   Mosberg Henry I HI  

ACS chemical biology 20111011 12


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 admin  ...[more]

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