Orally Active Adenosine A₁ 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 A_2AAR, A_2BAR, and A₃AR. 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 A₁AR knockout mice, revealing a strict dependence on A₁AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (<i>K</i>_i of 36 nM for the human A₁AR) make this compound potentially suitable as a therapeutic