Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists

Dilip K. Tosh, Antonella Ciancetta, Philip Mannes, Eugene Warnick, Aaron Janowsky, Amy J. Eshleman, Elizabeth Gizewski, Tarsis F. Brust, Laura M. Bohn, John A. Auchampach, Zhan Guo Gao, Kenneth A. Jacobson

Research output: Contribution to journalArticle

1 Citation (Scopus)

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, 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.

Original languageEnglish (US)
Pages (from-to)12658-12678
Number of pages21
JournalACS Omega
Volume3
Issue number10
DOIs
StatePublished - Jan 1 2018

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Purinergic P1 Receptor Agonists
Purinergic P1 Receptors
Narcotic Antagonists
Nucleosides
Scaffolds
Proteins
Adenosine A3 Receptor Agonists
Esters
Ribose
Opioid Receptors
Adenosine
Screening
Computer simulation

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Tosh, D. K., Ciancetta, A., Mannes, P., Warnick, E., Janowsky, A., Eshleman, A. J., ... Jacobson, K. A. (2018). Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists. ACS Omega, 3(10), 12658-12678. https://doi.org/10.1021/acsomega.8b01237

Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists. / Tosh, Dilip K.; Ciancetta, Antonella; Mannes, Philip; Warnick, Eugene; Janowsky, Aaron; Eshleman, Amy J.; Gizewski, Elizabeth; Brust, Tarsis F.; Bohn, Laura M.; Auchampach, John A.; Gao, Zhan Guo; Jacobson, Kenneth A.

In: ACS Omega, Vol. 3, No. 10, 01.01.2018, p. 12658-12678.

Research output: Contribution to journalArticle

Tosh, DK, Ciancetta, A, Mannes, P, Warnick, E, Janowsky, A, Eshleman, AJ, Gizewski, E, Brust, TF, Bohn, LM, Auchampach, JA, Gao, ZG & Jacobson, KA 2018, 'Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists', ACS Omega, vol. 3, no. 10, pp. 12658-12678. https://doi.org/10.1021/acsomega.8b01237
Tosh, Dilip K. ; Ciancetta, Antonella ; Mannes, Philip ; Warnick, Eugene ; Janowsky, Aaron ; Eshleman, Amy J. ; Gizewski, Elizabeth ; Brust, Tarsis F. ; Bohn, Laura M. ; Auchampach, John A. ; Gao, Zhan Guo ; Jacobson, Kenneth A. / Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists. In: ACS Omega. 2018 ; Vol. 3, No. 10. pp. 12658-12678.
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