A3 adenosine receptor agonists containing dopamine moieties for enhanced interspecies affinity.

Abstract

Following our study of 4'-truncated (N)-methanocarba-adenosine derivatives that displayed unusually high mouse (m) A3AR affinity, we incorporated dopamine-related N6 substituents in the full agonist 5'-methylamide series. N6-(2-(4-Hydroxy-3-methoxy-phenyl)ethyl) derivative MRS7618 11 displayed Ki (nM) 0.563 at hA3AR (∼20,000-fold selective) and 1.54 at mA3AR. 2-Alkyl ethers maintained A3 affinity, but with less selectivity than 2-alkynes. Parallel functional assays of G protein-dependent and β-arrestin 2 (βarr2)-dependent pathways indicate these are full agonists but not biased. Through use of computational modeling, we hypothesized that phenyl OH/OMe groups interact with polar residues, particularly Gln261, on the mA3AR extracellular loops as the basis for the affinity enhancement. Although the pharmacokinetics indicated facile clearance of parent O-methyl catechol nucleosides 21 and 31, prolonged mA3AR activation in vivo was observed in a hypothermia model, suggested potential formation of active metabolites through demethylation. Selected analogues induced mouse hypothermia following i.p. injection, indicative of peripheral A3AR agonism in vivo.

• Authors: Dilip K Tosh, Veronica Salmaso, Ryan G Campbell, Harsha Rao, Amelia Bitant, Eline Pottie, Christophe P Stove, Naili Liu, Oksana Gavrilova, Zhan-Guo Gao, John A Auchampach, Kenneth A Jacobson
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 228 Pg. 113983 (Jan 15 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 34844790 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Masson SAS.

Chemical References

• Adenosine A3 Receptor Agonists
• Receptor, Adenosine A3
• Dopamine

Topics

• Adenosine A3 Receptor Agonists (chemical synthesis, chemistry, pharmacology)
• Dopamine (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Receptor, Adenosine A3 (metabolism)
• Structure-Activity Relationship