TY - JOUR
T1 - Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists
AU - Tosh, Dilip K.
AU - Ciancetta, Antonella
AU - Mannes, Philip
AU - Warnick, Eugene
AU - Janowsky, Aaron
AU - Eshleman, Amy J.
AU - Gizewski, Elizabeth
AU - Brust, Tarsis F.
AU - Bohn, Laura M.
AU - Auchampach, John A.
AU - Gao, Zhan Guo
AU - Jacobson, Kenneth A.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/10/31
Y1 - 2018/10/31
N2 - 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, Ki ≈ 40 nM), revealed μOR 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.
AB - 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, Ki ≈ 40 nM), revealed μOR 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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U2 - 10.1021/acsomega.8b01237
DO - 10.1021/acsomega.8b01237
M3 - Article
AN - SCOPUS:85054509636
SN - 2470-1343
VL - 3
SP - 12658
EP - 12678
JO - ACS Omega
JF - ACS Omega
IS - 10
ER -