Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 10, Pages 1935-1941Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00637
Keywords
Adenosine receptor; G protein-coupled receptor; nucleosides; molecular dynamics; structure activity relationship
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Funding
- NIH Intramural Research Program (NIDDK) [ZIA DK031117]
- National Institutes of Health (NHLBI R01 grant) [HL133589]
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]
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A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as A(3)AR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse A(3)AR. The mean affinity enhancement for 5 pairs of 5'-methylamides was 11-fold at hA(3)AR and 42-fold at mA(3)AR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hA(3)AR-selective 16 (MRS7334) displaying K-i 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of 16 and its corresponding riboside 8 suggested a qualitative entropic advantage of 16 in hA(3)AR binding. The 5-F substitution tended to increase hA(3)AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist 4 was shown to interact potently exclusively with A(3)AR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for A(3)AR agonists, which have translational potential for chronic disease treatment.
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