Linked Life Data

11932067

Source:http://linkedlifedata.com/resource/pubmed/id/11932067

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
2002-4-4
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0304-3959
pubmed:author
pubmed:issnType
Print
pubmed:volume
96
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
107-18
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed-meshheading:11932067-Adenosine Kinase, pubmed-meshheading:11932067-Administration, Oral, pubmed-meshheading:11932067-Analgesics, pubmed-meshheading:11932067-Animals, pubmed-meshheading:11932067-Anti-Inflammatory Agents, pubmed-meshheading:11932067-Disease Models, Animal, pubmed-meshheading:11932067-Dose-Response Relationship, Drug, pubmed-meshheading:11932067-Enzyme Activation, pubmed-meshheading:11932067-Enzyme Inhibitors, pubmed-meshheading:11932067-Gastric Acid, pubmed-meshheading:11932067-Heart Rate, pubmed-meshheading:11932067-Hyperalgesia, pubmed-meshheading:11932067-Injections, Intraperitoneal, pubmed-meshheading:11932067-Motor Activity, pubmed-meshheading:11932067-Neuralgia, pubmed-meshheading:11932067-Nociceptors, pubmed-meshheading:11932067-Pyrimidines, pubmed-meshheading:11932067-Rats
pubmed:year
2002
pubmed:articleTitle
Analgesic and anti-inflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor.
pubmed:affiliation
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. michael.jarvis@abbott.com
pubmed:publicationType
Journal Article