Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters.
We have repurposed (N)-methanocarba adenosine derivatives (A3adenosine 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.
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.
Dilip K
DK
Tosh
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.
Aaron
A
Janowsky
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.
Amy J
AJ
Eshleman
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.
Eugene
E
Warnick
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.
Zhan-Guo
ZG
Gao
Department of Pharmacology and Physiology, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
Zhoumou
Z
Chen
Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
Elizabeth
E
Gizewski
Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
John A
JA
Auchampach
Department of Pharmacology and Physiology, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
Daniela
D
Salvemini
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.
Kenneth A
0000-0001-8104-1493
KA
Jacobson
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000819:agonists* / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000819:agonists* / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009705:Nucleosides; D058906:Purinergic P1 Receptor Agonists; D004298:Dopamine; D009638:Norepinephrine