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J Med Chem. 2012 Jul 26;55(14):6467-77. doi: 10.1021/jm3004834. Epub 2012 Jul 16.

Orally active adenosine A(1) receptor agonists with antinociceptive effects in mice.

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Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.


Adenosine A(1) receptor (A(1)AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A(1)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(1)AR agonists, some of which are structurally related to adenosine 5'-monophosphate (5'-AMP), a naturally occurring nucleotide that itself activates A(1)AR. These novel compounds potently activate A(1)AR in several orthogonal in vitro assays and are subtype selective for A(1)AR over A(2A)AR, A(2B)AR, and A(3)AR. 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 A(1)AR knockout mice, revealing a strict dependence on A(1)AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (K(i) of 36 nM for the human A(1)AR) make this compound potentially suitable as a therapeutic.

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