Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 228, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113983
Keywords
Adenosine receptor; G protein-coupled receptor; Nucleosides; Molecular modeling; Hypothermia; Structure activity relationship
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Funding
- NIH Intramural Research Program (NIDDK) [ZIADK031117]
- National Institutes of Health (NHLBI) [HL133589]
- (North Carolina at Chapel Hill)
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]
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By incorporating dopamine-related substituents, we have developed highly potent mouse A(3)AR agonists. Computational modeling and functional assays indicate that the enhanced affinity of these new compounds may be attributed to their interaction with polar residues on the mA(3)AR. Additionally, we observed peripheral A(3)AR agonism in vivo for these compounds.
Following our study of 4'-truncated (N)-methanocarba-adenosine derivatives that displayed unusually high mouse (m) A(3)AR affinity, we incorporated dopamine-related N-6 substituents in the full agonist 5'-methylamide series. N-6-(2-(4-Hydroxy-3-methoxy-phenyl)ethyl) derivative MRS7618 11 displayed K-i (nM) 0.563 at hA(3)AR (similar to 20,000-fold selective) and 1.54 at mA(3)AR. 2-Alkyl ethers maintained A(3) affinity, but with less selectivity than 2-alkynes. Parallel functional assays of G protein-dependent and beta-arrestin 2 (beta arr2)-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 mA(3)AR 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 mA(3)AR 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 A(3)AR agonism in vivo. (C) 2021 Published by Elsevier Masson SAS.
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