jm5b01998_si_002.csv (1.92 kB)
Purine (N)‑Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists
dataset
posted on 2016-02-18, 18:06 authored by Dilip
K. Tosh, Antonella Ciancetta, Eugene Warnick, Robert O’Connor, Zhoumou Chen, Elizabeth Gizewski, Steven Crane, Zhan-Guo Gao, John A. Auchampach, Daniela Salvemini, Kenneth A. JacobsonPurine
(N)-methanocarba-5′-N-alkyluronamidoriboside
A3 adenosine receptor (A3AR) agonists lacking
an exocyclic amine resulted from an unexpected
reaction during a Sonogashira coupling and subsequent aminolysis.
Because the initial C6-Me and C6-styryl derivatives had unexpectedly
high A3AR affinity, other rigid nucleoside analogues lacking
an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl)
and C2-(5-chlorothienylethynyl) analogues were particularly potent,
with human A3AR Ki values of
6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H
analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse
sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The
lack of a C6 H-bond donor while maintaining A3AR affinity
and efficacy could be rationalized by homology modeling and docking
of these hypermodified nucleosides. The modeling suggests that a suitable
combination of stabilizing features can partially compensate for the
lack of an exocyclic amine, an otherwise important contributor to
recognition in the A3AR binding site.