ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat.
Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC(50) = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED(50) = 5 micromol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED(50) = 70 micromol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 micromol/kg p.o.), mean arterial pressure (at 30-100 micromol/kg p.o.), or exploratory locomotor activity (at </=10 micromol/kg p.o.). Thus, ABT-702 is a novel, non-nucleoside AK inhibitor, with a nonopioid, non-nonsteroidal anti-inflammatory drug mechanism of action, which shows antinociceptive and anti-inflammatory activity in vivo.
Kowaluk
E A
EA
Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA.
Mikusa
J
J
Wismer
C T
CT
Zhu
C Z
CZ
Schweitzer
E
E
Lynch
J J
JJ
Lee
C H
CH
Jiang
M
M
Bhagwat
S S
SS
Gomtsyan
A
A
McKie
J
J
Cox
B F
BF
Polakowski
J
J
Reinhart
G
G
Williams
M
M
Jarvis
M F
MF
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D004487:Edema / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005557:Formaldehyde; D006439:Hemodynamics / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D013311:Streptozocin
D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D009025:Morpholines; D011743:Pyrimidines; D018047:Receptors, Purinergic P1; D005557:Formaldehyde; C416933:ABT 702; D013311:Streptozocin; D000248:Adenosine Kinase