%0 Online Multimedia %A Tosh, Dilip K. %A Salmaso, Veronica %A Rao, Harsha %A Campbell, Ryan %A Bitant, Amelia %A Gao, Zhan-Guo %A Auchampach, John A. %A Jacobson, Kenneth A. %D 2020 %T Direct Comparison of (N)-Methanocarba and Ribose-Containing 2‑Arylalkynyladenosine Derivatives as A3 Receptor Agonists %U https://acs.figshare.com/articles/media/Direct_Comparison_of_N_-Methanocarba_and_Ribose-Containing_2_Arylalkynyladenosine_Derivatives_as_A_sub_3_sub_Receptor_Agonists/11852604 %R 10.1021/acsmedchemlett.9b00637.s002 %2 https://acs.figshare.com/ndownloader/files/21724338 %K Molecular dynamics comparison %K hA 3 AR %K off-target activity profile %K MRS %K bicyclic pseudoribose ring constraint %K 5- F substitution %K 3 AR %K increase hA 3 AR affinity %K hA 3 AR binding %K representative methanocarba agonist 4 %K mA 3 AR %K 3 AR agonists %K 3 Receptor Agonists %K hA 3 AR-selective 16 %K GPCR %K K i 280 pM %X 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. %I ACS Publications