Biomedical subjects

M F Jarvis

Publications and source records attributed to M F Jarvis.

At least 19 recordsLinked to original sources

PubMed2005

Pharmacological characterization of P2X7 receptors in rat peritoneal cells.

OBJECTIVE AND DESIGN: P2X(7) receptor activation by ATP results in the release of IL-1beta and IL-18. Prolonged stimulation can lead to pore formation and cell death. In this study we pharmacologically characterized P2X(7) receptors on rat peritoneal cells (RPC) and on 1321N1 cells transfected with rat P2X(7) receptor (1321rP2X(7)-11). MATERIALS AND METHODS: RPC were isolated from rats by lavage. P2X(7) agonist induced pore formation in RPC was measured by EtBr uptake. P2X(7)-stimulated pore formation and Ca(++) influx in 1321rP2X(7)-11 cells were measured by a fluorometric imaging plate reader. The effects of pyridoxal phosphate-6-azo phenyl -2'-4'-disulfonic acid (PPADS) on pore formation and Ca(++) influx were examined in both RPC and 1321rP2X(7)-11. P2X(7)-mediated IL-1beta release in RPC and the effect of PPADS were determined. RESULTS: RPC express functional P2X(7) receptors that were activated by ATP analogs with a rank order of potency of 2'- 3'-O-(4-Benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) > ATP > alpha,beta-methylene ATP. Activation of P2X(7) receptors by BzATP was inhibited by PPADS. Similar results were also obtained in 1321rP2X(7)-11 cells. Activation of P2X(7) receptors on RPC resulted in IL-1 beta secretion, which was inhibited by PPADS. CONCLUSIONS: RPC express functional P2X(7) receptors that form pores and mediate the release of IL-1beta.

Adenosine Triphosphate↗

PubMed2005

Antinociceptive properties of a non-nucleotide P2X3/P2X2/3 receptor antagonist.

Acute systemic administration of a novel and highly selective non-nucleotide P2X(3)/P2X(2/3) receptor antagonist, A-317491, has been shown to reduce chronic hyperalgesia and allodynia in several animal models of pathological pain in the absence of cardiovascular and CNS side effects. Furthermore, these studies have also outlined the antinociceptive profile for a P2X(3)/P2X(2/3) receptor antagonist, as A-317491 was effective in models of chronic inflammatory and neuropathic pain, but not in models of acute, acute inflammatory or visceral pain. The development of A-317491 has also added to the current understanding of P2X(3)/P2X(2/3) receptor pharmacology and its contributions to nociceptive transmission and modulation. To this end, recent studies have demonstrated that both spinal and peripheral P2X(3)/P2X(2/3) receptors have significant but differential contributions to nociception in animal models of nerve or tissue injury, and that antagonism of spinal P2X(3)/P2X(2/3) receptors results in an indirect activation of the opioid system to alleviate inflammatory thermal hyperalgesia and chemogenic nociception. Thus, preclinical data have shown considerable promise for the utility of a P2X(3)/P2X(2/3) receptor antagonist to alleviate various forms of chronic pain. Furthermore, the discovery of this selective and metabolic stable antagonist for P2X(3)/P2X(2/3) receptors has also been useful in defining the contributions of these receptors to states of pathological pain.

Analgesics↗

PubMed2001

Synthesis and biological evaluation of clitocine analogues as adenosine kinase inhibitors.

Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.

Adenosine Kinase↗

PubMed2001

Pyridopyrimidine analogues as novel adenosine kinase inhibitors.

A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.

Adenosine Kinase↗

PubMed2001

A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats.

Extracellular levels of adenosine (ADO) can be raised through inhibition of adenosine kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors have shown antinociceptive activity in a variety of animal models of nociception. The present study investigated the antinociceptive actions of a novel and selective AK inhibitor, A-134974 (IC(50)=60 pM), in a rat model of neuropathic pain (ligations of the L5/L6 spinal nerves) and explored the relative contributions of supraspinal, spinal and peripheral sites to the actions of A-134974. Systemic A-134974 dose-dependently reduced tactile allodynia (ED(50)=5 micromol/kg, i.p.) for up to 2 h. Fall latencies in the rotorod test of motor coordination were unaffected by systemic administration of A-134974 (at doses up to 30 micromol/kg, i.p.). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50)=10 nmol) in relieving tactile allodynia than delivering the compound by intracerebroventricular (ED(50)>100 nmol, i.c.v.) or intraplantar (ED(50)>500 nmol) routes suggesting that spinal sites of action are the primary contributors to the anti-allodynic action of A-134974. The anti-allodynic effects of systemic A-134974 (10 micromol/kg, i.p.) were antagonized by the non-selective ADO receptor antagonist, theophylline (30-500 nmol) administered i.t. These data demonstrate that the novel AK inhibitor A-134974 potently reduces tactile allodynia through interactions with spinal sites and adds to the growing evidence that AK inhibitors may be useful as analgesic agents in a broad spectrum of pain states.

Adenosine Kinase↗

PubMed2001

Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor..

Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC(50) = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC(50) = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.

Adenosine Kinase↗

PubMed2001

Structure-activity studies of 5-substituted pyridopyrimidines as adenosine kinase inhibitors.

The synthesis and SAR of a novel series of non-nucleoside pyridopyrimidine inhibitors of the enzyme adenosine kinase (AK) are described. It was found that pyridopyrimidines with a broad range of medium and large non-polar substituents at the 5-position potently inhibited AK activity. A narrower range of analogues was capable of potently inhibiting adenosine phosphorylation in intact cells indicating an enhanced ability of these analogues to penetrate cell membranes. Potent AK inhibitors were found to effectively reduce nociception in animal models of thermal hyperalgesia and persistent pain.

Adenosine Kinase↗

PubMed2001

Modulation of BzATP and formalin induced nociception: attenuation by the P2X receptor antagonist, TNP-ATP and enhancement by the P2X(3) allosteric modulator, cibacron blue.

1. Exogenous ATP produces acute and localized pain in humans, and P2X receptor agonists elicit acute nociceptive behaviours in rodents following intradermal administration to the hindpaw. The predominant localization of P2X(3) mRNA in sensory neurones has led to the hypothesis that activation of P2X(3) and/or P2X(2/3) receptors contributes to nociception. 2. The local administration of the P2X receptor agonist, BzATP (100--1000 nmol paw(-1), s.c.) into the rat hindpaw produced an acute (<15 min) paw flinching response that was similar to that observed in the acute phase of the formalin (5%) test. 3. The co-administration of the potent P2X receptor antagonist, TNP-ATP (30--300 nmol paw(-1)), but not an inactive analogue, TNP-AMP, with BzATP into the rat hindpaw attenuated BzATP-induced nociception. Similarly, co-administration of TNP-ATP, but not TNP-AMP, with 5% formalin reduced both acute and persistent nociception in this test. 4. Co-administration of cibacron blue (30 and 100 nmol paw(-1)), a selective allosteric enhancer of P2X(3) and P2X(2/3) receptor activation, with BzATP (30 and 100 nmol paw(-1)) into the rat hindpaw produced significantly greater nociception as compared to the algogenic effects of BzATP alone. Intradermal co-administration of cibacron blue (30 and 100 nmol paw(-1)) with formalin (1 and 2.5%) into the rat hindpaw also produced significantly greater nociceptive behaviour as compared to formalin alone. 5. The ability of TNP-ATP and cibacron blue to respectively attenuate and enhance nociceptive responses elicited by exogenous BzATP and formalin provide further support for the hypothesis that activation of peripheral P2X(3) containing channels contributes specifically to both acute and persistent nociception in the rat.

Adenosine Triphosphate↗

PubMed2001

The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury.

1. Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside adenosine kinase (AK) inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT-702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain. 2. Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously following either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. 3. ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evoked responses in both carrageenan and nerve-injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT-702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance. 4. Protection of endogenous adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous adenosine-mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states.

Adenosine Kinase↗

PubMed2001

Recent developments in the discovery of novel adenosine kinase inhibitors: mechanism of action and therapeutic potential.

Adenosine (ADO) is an endogenous inhibitory neuromodulator that limits cellular excitability in response to tissue trauma and inflammation. Adenosine kinase (AK; EC 2.7.1.20) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. AK inhibitors have been shown to significantly increase ADO concentrations at sites of tissue injury and to provide effective antinociceptive, antiinflammatory, and anticonvulsant activity in animal models. Structurally novel nucleoside and non-nucleoside AK inhibitors that demonstrate high specificity for the AK enzyme compared with other ADO metabolic enzymes, transporters, and receptors have recently been synthesized. These compounds have also demonstrated improved cellular and tissue penetration compared with earlier tubercidin analogs. These compounds have been shown to exert beneficial effects in animal models of pain, inflammation and epilepsy with reduced cardiovascular side effects compared with direct acting ADO receptor (P1) agonists, thus supporting the hypothesis that AK inhibitors can enhance the actions of ADO in a site- and event-specific fashion.

Adenosine↗

PubMed2001

Anti-inflammatory effects of ABT-702, a novel non-nucleoside adenosine kinase inhibitor, in rat adjuvant arthritis.

Adenosine (ADO) is a homeostatic inhibitory autocoid that is released at sites of inflammation and tissue injury, and exerts anti-inflammatory effects via multiple interactions at ADO receptor subtypes. Inhibition of ADO kinase (AK) increases extracellular ADO concentrations and AK inhibitors have demonstrated ADO-mediated anti-inflammatory effects in acute models of inflammation. To evaluate the potential utility of this approach in chronic inflammation, a novel, potent, and selective non-nucleoside AK inhibitor, ABT-702, was tested in the rat adjuvant arthritis model. Animals were immunized with complete Freund's adjuvant on day 0 and were treated with vehicle or ABT-702 (20 mg/kg/b.i.d. p.o.) beginning on day 8. ABT-702 significantly inhibited arthritis as determined by paw volume. In addition, histologic and radiographic evidence of bone and cartilage destruction was significantly decreased in the treated group. Coadministration of the ADO receptor antagonist theophylline attenuated the anti-inflammatory effects of ABT-702, suggesting that this action was mediated through endogenous ADO release. To evaluate the mechanism of chondroprotection, Northern blot and electrophoretic mobility shift assays were performed on joints samples. These studies demonstrated that ABT-702 suppressed collagenase and stromelysin gene expression in treated animals. In addition, the activator protein-1 and nuclear factor-kappaB binding activity was also decreased. Therefore, ABT-702 inhibited clinical, radiographic, and histologic evidence of chronic inflammatory arthritis. The mechanism of joint protection is likely related to suppressed transcription factor activation and matrix metalloproteinase gene expression.

Adenosine↗

PubMed2001

Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action.

The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC(50) = 60 pM), in the carrageenan model of thermal hyperalgesia; 2) effects of A-134974 on locomotor activity; and 3) relative contributions of supraspinal, spinal, and peripheral sites to the actions of A-134974. Systemic A-134974 (i.p.) dose dependently reduced hyperalgesia (ED(50) = 1 micromol/kg) and at higher doses, reduced locomotor activity (ED(50) = 16 micromol/kg). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50) = 6 nmol) at producing antihyperalgesia than delivering the compound by intracerebralventricular (ED(50) = 100 nmol, i.c.v.) or intraplantar (ED(50) >300 nmol) routes. In contrast, i.c.v. administration of A-134974 was more effective in reducing locomotor activity than i.t. administration (ED(50) values were 1 and >100 nmol, respectively). Increasing the pretreatment time for i.t.-delivered A-134974 caused a greater reduction in locomotor activity (ED(50) = 10 nmol). This was due to diffusion of A-134974 (i.t.) to supraspinal sites. The antihyperalgesic effects of systemic A-134974 were antagonized by the adenosine receptor antagonist theophylline (THEO, 30-500 nmol) administered i.t., but not i.c.v. In the locomotor assay, i.t.-injected THEO did not antagonize hypomobility caused by systemic or i.t. administration of A-134974. However, i.c.v. infusion of THEO did block the hypomotive actions of i.c.v.-, i.t.-, and i.p.-administered A-134974. These data demonstrate that the novel AK inhibitor A-134974 potently reduces thermal hyperalgesia primarily through interactions with spinal sites, whereas its ability to depress locomotor activity is predominantly mediated by supraspinal sites.

Adenosine Kinase↗

PubMed2000

Design of adenosine kinase inhibitors from the NMR-based screening of fragments.

A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization.

Adenosine Kinase↗

PubMed2000

Purinergic and pyrimidinergic receptors as potential drug targets.

In the last decade, the field of purinergic pharmacology has continued to grow as the complexity of the receptor families and the various enzymes involved in purine metabolism have been defined in molecular terms. A major theme that has emerged from these studies is the functional complexity of the interactions between P1 and P2 receptors, based upon the dynamic interrelationship between ATP and adenosine as extracellular signaling molecules. It is now clear that ATP and its degradation products (particularly ADP and adenosine) form a complex cascade for the regulation of cell-to-cell communication that can function to attenuate the consequences of tissue trauma (e.g. ischemia) that involve alterations in cellular energy charge and depletion of ATP stores. In addition to the P2 receptor family, alterations in cellular ATP stores can also affect the function of other receptors, e.g. K(ATP) channels, and mitochondrial function. The discovery of pyrimidine-preferring (UTP/UDP) P2Y receptors has also raised the possibility that the corresponding nucleoside, uracil, may function as a signaling molecule.

Animals↗

PubMed2000

ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain.

Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (</=8.0 g). Systemic (i.p.) administration of ABT-627 (1 and 10 mg/kg) was found to produce a dose-dependent increase in tactile allodynia thresholds. A significant antinociceptive effect (40-50% increase in tactile allodynia thresholds, P<0.05) was observed at the dose of 10 mg/kg, i.p., within 0.5-2-h post-dosing. The antinociceptive effects of ABT-627 (10 mg kg(-1) day(-1), p.o.) were maintained following chronic administration of the antagonist in drinking water for 7 days. In comparison, morphine administered acutely at a dose of 8 mg/kg, i.p., produced a significant 90% increase in streptozotocin-induced tactile allodynia thresholds. The endothelin ET(B) receptor-selective antagonist, 2R-(4-propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allodynia thresholds in streptozotocin-treated rats. Although combined i.p. administration of ABT-627 and A-192621 produced a significant, acute increase in tactile allodynia thresholds, this effect was significantly less than that produced by ABT-627 alone. These results indicate that the selective blockade of endothelin ET(A) receptors results in an attenuation of tactile allodynia in the streptozotocin-treated rat.

Analgesics, Non-Narcotic↗

PubMed2000

Competitive antagonism of recombinant P2X(2/3) receptors by 2', 3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP).

TNP-ATP has become widely recognized as a potent and selective P2X receptor antagonist, and is currently being used to discriminate between subtypes of P2X receptors in a variety of tissues. We have investigated the ability of TNP-ATP to inhibit alpha,beta-methylene ATP (alpha,beta-meATP)-evoked responses in 1321N1 human astrocytoma cells expressing recombinant rat or human P2X(2/3) receptors. Pharmacological responses were measured using electrophysiological and calcium imaging techniques. TNP-ATP was a potent inhibitor of P2X(2/3) receptors, blocking both rat and human receptors with IC(50) values of 3 to 6 nM. In competition studies, 10 to 1000 microM alpha,beta-meATP was able to overcome TNP-ATP inhibition. Schild analysis revealed that TNP-ATP was a competitive antagonist with pA(2) values of -8.7 and -8.2. Inhibition of P2X(2/3) receptors by TNP-ATP was rapid in onset, reversible, and did not display use dependence. Although the onset kinetics of inhibition were concentration-dependent, the TNP-ATP off-kinetics were concentration-independent and relatively slow. Full recovery from TNP-ATP inhibition did not occur until >/=5 s after removal of the antagonist. Because of the slow off-kinetics of TNP-ATP, full competition with alpha,beta-meATP for receptor occupancy could be seen only after both ligands had reached a steady-state condition. It is proposed that the slowly desensitizing P2X(2/3) receptor allowed this competitive interaction to be observed over time, whereas the rapid desensitization of other P2X receptors (P2X(3)) may mask the detection of competitive inhibition by TNP-ATP.

Adenosine Triphosphate↗

PubMed2000

Therapeutic potential of adenosine kinase inhibitors.

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra and extracellular concentrations of adenosine (ADO), an endogenous modulator of intercellular signalling that reduces cell excitability during tissue stress and trauma. The inhibitory effects of ADO are mediated by interactions with specific cell-surface G-protein coupled receptors (GPCR), which regulate membrane cation flux, membrane polarisation and the release of excitatory neurotransmitters. Inhibition of AK potentiates local extracellular ADO levels at cell and tissue sites which are undergoing accelerated ADO release. Thus, AK inhibition represents a mechanism to selectively enhance the endogenous protective actions of ADO during cellular stress while potentially minimising the non-specific effects associated with the systemic administration of ADO receptor agonists. Novel, potent AK inhibitors have recently been synthesised that demonstrate high specificity for this particular enzyme as compared to other ADO metabolic enzymes, transporters and receptors. AK inhibitors have been shown to increase ADO concentrations in various systems in vitro, as well as in an in vivo model of neurotoxicity. In addition, AK inhibitors have demonstrated efficacy in animal models of epilepsy, cerebral ischaemia as well as pain and inflammation, thus suggesting their potential therapeutic utility for these conditions.

Adenosine Kinase↗

PubMed2000

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 anti-inflammatory properties: I. In vitro characterization and acute antinociceptive effects in the mouse.

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 (IC(50) = 1. 7 nM) non-nucleoside AK inhibitor that has several orders of magnitude selectivity over other sites of ADO interaction (A(1), A(2A), A(3) 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 (IC(50) = 1.5 +/- 0. 3 nM) in inhibiting native human AK (placenta), two human recombinant isoforms (AK(long) and AK(short)), 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 MgATP(2-). 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 (ED(50) = 8 micromol/kg i.p.; 65 micromol/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 A(1)-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 A(2A)-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 A(1) receptor-mediated mechanism.

Adenosine Kinase↗