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ACS Omega. 2018 Oct 31;3(10):12658-12678. doi: 10.1021/acsomega.8b01237. Epub 2018 Oct 4.

Repurposing of a Nucleoside Scaffold from Adenosine Receptor Agonists to Opioid Receptor Antagonists.

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Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
VA Portland Health Care System, Research Service (R&D-22), and Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University, 3710 S.W. U.S. Veterans Hospital Blvd., Portland, Oregon 97239, United States.
Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.


While screening off-target effects of rigid (N)-methanocarba-adenosine 5'-methylamides as A3 adenosine receptor (AR) agonists, we discovered μM binding hits at the δ-opioid receptor (DOR) and translocator protein (TSPO). In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at κ-(K)OR appeared in 5'-esters (ethyl 24 and propyl 30), which retained TSPO interaction (μM). 7-Deaza modification of C2-(arylethynyl)-5'-esters but not 4'-truncation enhanced KOR affinity (MRS7299 28 and 29, K i ≈ 40 nM), revealed μ-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3-Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis for KOR recognition.

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