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Medchemcomm. 2018 Oct 18;9(11):1920-1932. doi: 10.1039/c8md00317c. eCollection 2018 Nov 1.

Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A3 adenosine receptor antagonists.

Author information

1
Molecular Recognition Section , Laboratory of Bioorganic Chemistry , National Institute of Diabetes and Digestive and Kidney Diseases , National Institutes of Health , Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC , Bethesda , Maryland 20892-0810 , USA . Email: kennethj@niddk.nih.gov ; ; Tel: +301 496 9024.
2
School of Pharmacy , Queen's University Belfast , 96 Lisburn Rd , Belfast , BT9 7BL , UK.
3
Department of Pharmacology , Medical College of Wisconsin , 8701 Watertown Plank Road , Milwaukee , Wisconsin 53226 , USA.

Abstract

Recognition of nucleosides at adenosine receptors (ARs) is supported by multiple X-ray structures, but the structure of an adenine complex is unknown. We examined the selectivity of predicted A1AR and A3AR adenine antagonists that incorporated known agonist affinity-enhancing N 6 and C2 substituents. Adenines with A1AR-favoring N 6-alkyl, cycloalkyl and arylalkyl substitutions combined with an A3AR-favoring 2-((5-chlorothiophen-2-yl)ethynyl) group were human (h) A3AR-selective, e.g. MRS7497 17 (∼1000-fold over A1AR). In addition, binding selectivity over hA2AAR and hA2BAR and functional A3AR antagonism were demonstrated. 17 was subjected to computational docking and molecular dynamics simulation in a hA3AR homology model to predict interactions. The SAR of nucleoside AR agonists was not recapitulated in adenine AR antagonists, and modeling suggested an alternative, inverted binding mode with the key N2506.55 H-bonding to the adenine N 3 and N 9, instead of N 6 and N 7 as in adenosine agonists.

PMID:
30568760
PMCID:
PMC6256369
[Available on 2019-10-18]
DOI:
10.1039/c8md00317c

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