1. Discovery, Synthesis, and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor.
- Author
-
Neil T. Burford, Kathryn E. Livingston, Meritxell Canals, Molly R. Ryan, Lauren M. L. Budenholzer, Ying Han, Yi Shang, John J. Herbst, Jonathan O’Connell, Martyn Banks, Litao Zhang, Marta Filizola, Daniel L. Bassoni, Tom S. Wehrman, Arthur Christopoulos, John R. Traynor, Samuel W. Gerritz, and Andrew Alt
- Subjects
- *
MOLECULAR pharmacology , *ALLOSTERIC regulation , *OPIOID receptors , *CHEMICAL synthesis , *G protein coupled receptors , *DRUG overdose - Abstract
Allosteric modulators of G protein-coupledreceptors (GPCRs) have a number of potential advantages compared toagonists or antagonists that bind to the orthosteric site of the receptor.These include the potential for receptor selectivity, maintenanceof the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allostericcooperativity which may prevent overdose issues, and engendering biasby differentially modulating distinct signaling pathways. Here wedescribe the discovery, synthesis, and molecular pharmacology of δ-opioidreceptor-selective positive allosteric modulators (δ PAMs).These δ PAMs increase the affinity and/or efficacy of the orthostericagonists leu-enkephalin, SNC80 and TAN67, as measured by receptorbinding, G protein activation, β-arrestin recruitment, adenylylcyclase inhibition, and extracellular signal-regulated kinases (ERK)activation. As such, these compounds are useful pharmacological toolsto probe the molecular pharmacology of the δ receptor and toexplore the therapeutic potential of δ PAMs in diseases suchas chronic pain and depression. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF