Analgesic and anti-inflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor.
Adenosine (ADO) is an inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibition of the ADO-metabolizing enzyme, adenosine kinase (AK) increases extracellular ADO concentrations at sites of tissue trauma and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. N7-((1'R,2'S,3'R,4'S)-2',3'-dihydroxy-4'-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo[2,3-a]pyrimidine (A-286501) is a novel and potent (IC50=0.47 nM) carbocyclic nucleoside AK inhibitor that has no significant activity (IC50 >100 microM) at other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase) or other (IC50 value >10 microM) neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter reuptake sites and enzymes, including cyclooxygenases-1 and -2. A-286501 showed equivalent potency to inhibit AK from several mammalian species and kinetic studies revealed that A-286501 was a reversible and competitive inhibitor with respect to ADO and non-competitive with respect to MgATP2-. A-286501 was orally effective to reduce nociception in animal models of acute (thermal), inflammatory (formalin and carrageenan), and neuropathic (L5/L6 nerve ligation and streptozotocin-induced diabetic) pain. A-286501 was particularly potent (ED50=1 micromol/kg, p.o.) to reduce carrageenan-induced inflammatory thermal hyperalgesia as compared to its analgesic actions in other pain models (acute and neuropathic) and its ability to alter hemodynamic function and motor performance. A-286501 was also effective to reduce carrageenan-induced paw edema and myeloperoxidase activity, a measure of neutrophil influx (ED50=10 micromol/kg, p.o.), in the injured paw. The anti-nociceptive effects of A-286501 in the L5/L6 nerve injury model of neuropathic pain (ED50=20 micromol/kg, p.o.) were not blocked by the opioid antagonist naloxone, but were blocked by the ADO receptor antagonist, theophylline. Following repeated administration, A-286501 showed less potential to produce tolerance as compared to morphine. Thus, A-286501 is a structurally novel AK inhibitor that effectively attenuates nociception by a non-opioid, non-non-steroidal anti-inflammatory drug ADO, receptor mediated mechanism.
Jarvis
Michael F
MF
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. michael.jarvis@abbott.com
Yu
Haixia
H
McGaraughty
Steve
S
Wismer
Carol T
CT
Mikusa
Joe
J
Zhu
Chang
C
Chu
Katharine
K
Kohlhaas
Kathy
K
Cowart
Marlon
M
Lee
Chih Hung
CH
Stewart
Andrew O
AO
Cox
Bryan F
BF
Polakowski
James
J
Kowaluk
Elizabeth A
EA
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005744:Gastric Acid; D006339:Heart Rate / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy*; D007274:Injections, Intraperitoneal; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy; D009619:Nociceptors / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; C461484:N7-((1'R,2'S,3'R,4'S)-2',3'-dihydroxy-4'-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo(2,3-a)pyrimidine; D000248:Adenosine Kinase