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J Med Chem. 2017 Apr 13;60(7):3109-3123. doi: 10.1021/acs.jmedchem.7b00141. Epub 2017 Mar 20.

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

Author information

1
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 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 , Portland, Oregon 97239, United States.
3
Department of Pharmacology and Physiology, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
4
Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.

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.

PMID:
28319392
PMCID:
PMC5501184
DOI:
10.1021/acs.jmedchem.7b00141
[Indexed for MEDLINE]
Free PMC Article

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