3 research outputs found
Orally Active Adenosine A 1 Receptor Agonists with Antinociceptive Effects in Mice
Adenosine A1 receptor (A1AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A1AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A1AR agonists, some of which are structurally related to adenosine 5′-monophosphate (5′-AMP), a naturally occurring nucleotide that itself activates A1AR. These novel compounds potently activate A1AR in several orthogonal in vitro assays and are subtype selective for A1AR over A2AAR, A2BAR, and A3AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A1AR knockout mice, revealing a strict dependence on A1AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (Ki of 36 nM for the human A1AR) make this compound potentially suitable as a therapeutic
Orally Active Adenosine A<sub>1</sub> Receptor Agonists with Antinociceptive Effects in Mice
Adenosine A<sub>1</sub> receptor (A<sub>1</sub>AR) agonists
have
antinociceptive effects in multiple preclinical models of acute and
chronic pain. Although numerous A<sub>1</sub>AR agonists have been
developed, clinical applications of these agents have been hampered
by their cardiovascular side effects. Herein we report a series of
novel A<sub>1</sub>AR agonists, some of which are structurally related
to adenosine 5′-monophosphate (5′-AMP), a naturally
occurring nucleotide that itself activates A<sub>1</sub>AR. These
novel compounds potently activate A<sub>1</sub>AR in several orthogonal
in vitro assays and are subtype selective for A<sub>1</sub>AR over
A<sub>2A</sub>AR, A<sub>2B</sub>AR, and A<sub>3</sub>AR. Among them,
UNC32A (<b>3a</b>) is orally active and has dose-dependent antinociceptive
effects in wild-type mice. The antinociceptive effects of <b>3a</b> were completely abolished in A<sub>1</sub>AR knockout mice, revealing
a strict dependence on A<sub>1</sub>AR for activity. The apparent
lack of cardiovascular side effects when administered orally and high
affinity (<i>K</i><sub>i</sub> of 36 nM for the human A<sub>1</sub>AR) make this compound potentially suitable as a therapeutic