Orally active adenosine A(1) receptor agonists with antinociceptive effects in mice.
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.
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.
Ilia
I
Korboukh
Emily A
EA
Hull-Ryde
Joseph E
JE
Rittiner
Amarjit S
AS
Randhawa
Jennifer
J
Coleman
Brendan J
BJ
Fitzpatrick
Vincent
V
Setola
William P
WP
Janzen
Stephen V
SV
Frye
Mark J
MJ
Zylka
Jian
J
Jin
D058907:Adenosine A1 Receptor Agonists / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000249:Adenosine Monophosphate / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013379:Substrate Specificity; D013696:Temperature
D058907:Adenosine A1 Receptor Agonists; D000700:Analgesics; D043682:Receptor, Adenosine A1; D000249:Adenosine Monophosphate