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

ABSTRACT: 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 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

SUBMITTER: Tosh DK 

PROVIDER: S-EPMC7549272 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature