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.