%0 DATA
%A Dilip
K., Tosh
%A Veronica, Salmaso
%A Harsha, Rao
%A Ryan, Campbell
%A Amelia, Bitant
%A Zhan-Guo, Gao
%A John A., Auchampach
%A Kenneth A., Jacobson
%D 2020
%T Direct Comparison of (N)-Methanocarba and Ribose-Containing
2‑Arylalkynyladenosine Derivatives as A_{3} Receptor
Agonists
%U https://acs.figshare.com/articles/dataset/Direct_Comparison_of_N_-Methanocarba_and_Ribose-Containing_2_Arylalkynyladenosine_Derivatives_as_A_sub_3_sub_Receptor_Agonists/11852616
%R 10.1021/acsmedchemlett.9b00637.s006
%2 https://acs.figshare.com/ndownloader/files/21724350
%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 A_{3}AR agonists indicated
that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity
at human and mouse A_{3}AR. The mean affinity enhancement
for 5 pairs of 5′-methylamides was 11-fold at hA_{3}AR and 42-fold at mA_{3}AR. Novel C2-(5-fluorothien-2-ylethynyl)
substitution enhanced affinity in the methanocarba but not ribose
series, with highly hA_{3}AR-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 hA_{3}AR binding. The 5-F substitution tended to increase hA_{3}AR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives.
A representative methanocarba agonist **4** was shown to
interact potently exclusively with A_{3}AR, among 240 GPCRs
and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba
modification has distinct advantages for A_{3}AR agonists,
which have translational potential for chronic disease treatment.