Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

Dilip K. Tosh, Aaron Janowsky, Amy J. Eshleman, Eugene Warnick, Zhan Guo Gao, Zhoumou Chen, Elizabeth Gizewski, John A. Auchampach, Daniela Salvemini, Kenneth A. Jacobson

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

We have repurposed (N)-methanocarba adenosine derivatives (A3 adenosine receptor (AR) agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure-activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter transporter activity of rigid nucleosides while reducing A3AR affinity.

Original languageEnglish (US)
Pages (from-to)3109-3123
Number of pages15
JournalJournal of Medicinal Chemistry
Volume60
Issue number7
DOIs
StatePublished - Apr 13 2017

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Purinergic P1 Receptor Agonists
Norepinephrine Plasma Membrane Transport Proteins
Symporters
Ribose
Nucleosides
Human Activities
Adenosine A3 Receptor Agonists
Dopamine
Norepinephrine
Esters
Neurotransmitter Transport Proteins
Sodium
Dopamine Plasma Membrane Transport Proteins
Adenine
Structure-Activity Relationship
Cocaine
Adenosine
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists) : Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters. / Tosh, Dilip K.; Janowsky, Aaron; Eshleman, Amy J.; Warnick, Eugene; Gao, Zhan Guo; Chen, Zhoumou; Gizewski, Elizabeth; Auchampach, John A.; Salvemini, Daniela; Jacobson, Kenneth A.

In: Journal of Medicinal Chemistry, Vol. 60, No. 7, 13.04.2017, p. 3109-3123.

Research output: Contribution to journalArticle

Tosh, DK, Janowsky, A, Eshleman, AJ, Warnick, E, Gao, ZG, Chen, Z, Gizewski, E, Auchampach, JA, Salvemini, D & Jacobson, KA 2017, 'Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters', Journal of Medicinal Chemistry, vol. 60, no. 7, pp. 3109-3123. https://doi.org/10.1021/acs.jmedchem.7b00141
Tosh, Dilip K. ; Janowsky, Aaron ; Eshleman, Amy J. ; Warnick, Eugene ; Gao, Zhan Guo ; Chen, Zhoumou ; Gizewski, Elizabeth ; Auchampach, John A. ; Salvemini, Daniela ; Jacobson, Kenneth A. / Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists) : Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 7. pp. 3109-3123.
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