10.1021/acsmedchemlett.9b00637.s003 Dilip K. Tosh Dilip K. Tosh Veronica Salmaso Veronica Salmaso Harsha Rao Harsha Rao Ryan Campbell Ryan Campbell Amelia Bitant Amelia Bitant Zhan-Guo Gao Zhan-Guo Gao John A. Auchampach John A. Auchampach Kenneth A. Jacobson Kenneth A. Jacobson Direct Comparison of (N)-Methanocarba and Ribose-Containing 2‑Arylalkynyladenosine Derivatives as A<sub>3</sub> Receptor Agonists American Chemical Society 2020 Molecular dynamics comparison hA 3 AR off-target activity profile MRS bicyclic pseudoribose ring constraint 5- F substitution 3 AR increase hA 3 AR affinity hA 3 AR binding representative methanocarba agonist 4 mA 3 AR 3 AR agonists 3 Receptor Agonists hA 3 AR-selective 16 GPCR K i 280 pM 2020-02-13 22:44:09 Media https://acs.figshare.com/articles/media/Direct_Comparison_of_N_-Methanocarba_and_Ribose-Containing_2_Arylalkynyladenosine_Derivatives_as_A_sub_3_sub_Receptor_Agonists/11852607 A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]­hexane) nucleosides as A<sub>3</sub>AR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse A<sub>3</sub>AR. The mean affinity enhancement for 5 pairs of 5′-methylamides was 11-fold at hA<sub>3</sub>AR and 42-fold at mA<sub>3</sub>AR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hA<sub>3</sub>AR-selective <b>16</b> (MRS7334) displaying K<sub>i</sub> 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of <b>16</b> and its corresponding riboside <b>8</b> suggested a qualitative entropic advantage of <b>16</b> in hA<sub>3</sub>AR binding. The 5-F substitution tended to increase hA<sub>3</sub>AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist <b>4</b> was shown to interact potently exclusively with A<sub>3</sub>AR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for A<sub>3</sub>AR agonists, which have translational potential for chronic disease treatment.