Format

Send to

Choose Destination
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.

Author information

1
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.
2
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.
3
Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
4
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.

Abstract

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.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center