ml9b00637_si_003.avi (12.75 MB)
Download file

Direct Comparison of (N)-Methanocarba and Ribose-Containing 2‑Arylalkynyladenosine Derivatives as A3 Receptor Agonists

Download (12.75 MB)
posted on 13.02.2020, 22:44 by Dilip K. Tosh, Veronica Salmaso, Harsha Rao, Ryan Campbell, Amelia Bitant, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]­hexane) nucleosides as A3AR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse A3AR. The mean affinity enhancement for 5 pairs of 5′-methylamides was 11-fold at hA3AR and 42-fold at mA3AR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hA3AR-selective 16 (MRS7334) displaying Ki 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 hA3AR binding. The 5-F substitution tended to increase hA3AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist 4 was shown to interact potently exclusively with A3AR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for A3AR agonists, which have translational potential for chronic disease treatment.