ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholinopyridin-3-yl) pyrido [2, 3-d] pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and …

MF Jarvis, H Yu, K Kohlhaas, K Alexander… - … of Pharmacology and …, 2000 - ASPET
MF Jarvis, H Yu, K Kohlhaas, K Alexander, CH Lee, M Jiang, SS Bhagwat, M Williams
Journal of Pharmacology and Experimental Therapeutics, 2000ASPET
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. ABT-
702 is a novel and potent (IC50= 1.7 nM) non-nucleoside AK inhibitor that has several
orders of magnitude selectivity over other sites of ADO interaction (A1, A2A, A3 receptors …
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. ABT-702 is a novel and potent (IC50 = 1.7 nM) non-nucleoside AK inhibitor that has several orders of magnitude selectivity over other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase). ABT-702 was 1300- to 7700-fold selective for AK compared with a number of other neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter/nucleoside reuptake sites, and enzymes, including cycloxygenases-1 and -2. ABT-702 was equipotent (IC50 = 1.5 ± 0.3 nM) in inhibiting native human AK (placenta), two human recombinant isoforms (AKlong and AKshort), and AK from monkey, dog, rat, and mouse brain. Kinetic studies revealed that AK inhibition by ABT-702 was competitive with respect to ADO and noncompetitive with respect to MgATP2−. AK inhibition by ABT-702 was demonstrated to be reversible after 4 h of dialysis. ABT-702 is orally active and fully efficacious in reducing acute somatic nociception (ED50 = 8 μmol/kg i.p.; 65 μmol/kg p.o.) in the mouse hot-plate assay. ABT-702 also dose dependently reduced nociception in the phenyl-p-quinone-induced abdominal constriction assay. The antinociceptive effects of ABT-702 in the hot-plate assay were blocked by the nonselective ADO receptor antagonist theophylline, and by the A1-selective antagonist cyclopentyltheophylline (10 mg/kg i.p.), but not by a peripherally selective ADO receptor antagonist 8-(p-sulfophenyl)-theophylline (50 mg/kg i.p.), by the A2A-selective antagonist 3,7-dimethyl-1-propargylxanthine (1 mg/kg i.p.) or the opioid antagonist naloxone (5 mg/kg i.p.). Thus, ABT-702 is a novel and potent non-nucleoside AK inhibitor that effectively reduces acute thermal nociception in the mouse by a nonopioid, non-nonsteroidal anti-inflammatory drug, ADO A1 receptor-mediated mechanism.
ASPET