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

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Korboukh I, Hull-Ryde EA, Rittiner JE, Randhawa AS, Coleman J, Fitzpatrick BJ, Setola V, Janzen WP, Frye SV, Zylka MJ, Jin J

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

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

PubMed ID

22738238 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Adenosine	Adenosine receptor A1	EC 50 (nM)	1410	N/A	N/A	Details
Adenosine	Adenosine receptor A1	EC 50 (nM)	39	N/A	N/A	Details