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.

Abstract

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.

• Authors: E A Kowaluk, J Mikusa, C T Wismer, C Z Zhu, E Schweitzer, J J Lynch, C H Lee, M Jiang, S S Bhagwat, A Gomtsyan, J McKie, B F Cox, J Polakowski, G Reinhart, M Williams, M F Jarvis
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 295 Issue 3 Pg. 1165-74 (Dec 2000) ISSN: 0022-3565 [Print] United States
• PMID: 11082454 (Publication Type: Journal Article)

Chemical References

• Analgesics, Non-Narcotic
• Anti-Inflammatory Agents, Non-Steroidal
• Enzyme Inhibitors
• Morpholines
• Pyrimidines
• Receptors, Purinergic P1
• Formaldehyde
• ABT 702
• Streptozocin
• Adenosine Kinase

Topics

• Adenosine Kinase (antagonists & inhibitors)
• Administration, Oral
• Analgesics, Non-Narcotic (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Diabetes Mellitus, Experimental (physiopathology)
• Edema (drug therapy)
• Enzyme Inhibitors (pharmacology)
• Formaldehyde
• Hemodynamics (drug effects)
• Hyperalgesia (drug therapy)
• Male
• Morpholines (pharmacology)
• Motor Activity (drug effects)
• Pain (drug therapy)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P1 (drug effects)
• Streptozocin