%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