期刊
ACS OMEGA
卷 3, 期 10, 页码 12658-12678出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.8b01237
关键词
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资金
- NIH Intramural Research Program (NIDDK) [ZIA DK031117-28]
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]
- NIH National Institute on Drug Abuse (NIDA)/VA Interagency Agreement [ADA12013]
- Department of Veterans Affairs Research Career Scientist and Merit Review Programs
- NIDA [R01DA031297]
- Methamphetamine Abuse Research Center [P50 DA018165-06]
While screening off-target effects of rigid (N)-methanocarba-adenosine 5'-methylamides as A(3) adenosine receptor (AR) agonists, we discovered mu M binding hits at the d-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 kappa-(K)OR appeared in 5'-esters (ethyl 24 and propyl 30), which retained TSPO interaction (mu M). 7-Deaza modification of C2-(arylethynyl)-5'-esters but not 4'-truncation enhanced KOR affinity (MRS7299 28 and 29, K-1 approximate to 40 nM), revealed mu-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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