UMLS:C0030193 - FACTA Search

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Query: UMLS:C0030193 (pain)
261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats. 1142 84

Relevant aspects of pain physiology and anatomy are reviewed, including hyperalgesia (an exaggerated response to normally mild stimuli) and allodynia (pain in response to normally non-noxious stimuli). Although the principal animal models do an excellent job at separating thermal, mechanoreceptor, and visceral aspects of pain, they are not very good predictive models because human pain is more complex. Human pain includes overlapping aspects of specific pain types, such as spontaneous and induced pain, and is modified by gender, stress, states of vigilance, and depression. Nonsteroidal anti-inflammatory drugs (NSAIDs) have both peripheral and central analgesic effects. While prostaglandin-mediated effects are clearly operative, there are also other potential mechanisms involved in many cases and these may be quite important in certain patients. Effects mediated by cyclooxygenase-1, leukotriene B4, and intracellular transcription elements such as peroxisomal proliferator-activated receptors gamma (PPARgamma) may account for part of the spectrum of NSAID actions. Future directions for analgesic research are many, but include the use of nitric oxide (NO) NSAIDs; the possibility of decreasing NO in the central nervous system; inhibiting the vanilloid receptor-1; inhibiting adenosine kinase; activating PPARgamma; and mimicking superoxide dismutase, as well as combinations of complementary-acting analgesics.
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PMID:Future directions in pain management. 1169 56

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.
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PMID:Recent developments in the discovery of novel adenosine kinase inhibitors: mechanism of action and therapeutic potential. 1183 Jul 58

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.
Pain 2002 Mar
PMID:Analgesic and anti-inflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor. 1193 67

Inhibitors of adenosine kinase (AK) enhance extracellular concentrations of the inhibitory neuromodulator adenosine (ADO) at sites of tissue hyperexcitability and produce antinociceptive effects in animal models of pain and inflammation. The present study compared the ability of several novel and selective AK inhibitors and ADO receptor-selective agonists to attenuate carrageenan-induced thermal hyperalgesia and to impair motor performance as measured by effects on exploratory motor activity and rotorod performance. The prototypical nucleoside AK inhibitor, 5'deoxy-5-iodotubercidin (5'd-5IT), dose-dependently blocked thermal hyperalgesia (ED(50)=0.2 micromol/kg ip) and was 4- and 75-fold less potent in reducing exploratory motor activity and rotorod performance, respectively. The antihyperalgesic effects of 5'd-5IT were fully blocked by the A(1) antagonist, cyclopentyltheophylline (CPT) and the A(2A) antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX). Novel nucleoside and non-nucleoside AK inhibitors (A-134974, A-286501 and ABT-702) also potently (ED(50)=0.7-2 micromol/kg ip) blocked carrageenan-induced thermal hyperalgesia and were significantly less potent than 5'd-5IT in impairing motor performance. The systemic administration of N(6)-cyclopentyladenosine (CPA), an A(1) receptor-selective agonist, CGS 21680, an A(2A) receptor-selective agonist, and N(6)-ethylcarboxamidoadenosine (NECA), a nonselective ADO receptor agonist potently reduced (ED(50)=0.3-1.0 micromol/kg ip) thermal hyperalgesia. Unlike the AK inhibitors, however, these ADO receptor agonists produced significant antinociception only at doses that also decreased motor performance. These data demonstrate that AK inhibitors produce specific antihyperalgesic effects via an interaction with ADO A(1) and A(2A) receptors at doses that lack detectable effects on exploratory motor activity and rotorod performance and offer an improved separation between antinociceptive and motor impairing effects as compared to ADO receptor agonists.
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PMID:Comparison of the ability of adenosine kinase inhibitors and adenosine receptor agonists to attenuate thermal hyperalgesia and reduce motor performance in rats. 1215 Oct 32

Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
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PMID:Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors. 1216 37

Modulation of endogenous adenosine levels by inhibition of adenosine metabolism produces a peripheral antinociceptive effect in a neuropathic pain model. The present study used microdialysis to investigate the neuronal mechanisms modulating extracellular adenosine levels in the rat hind paw following tight ligation of the L5 and L6 spinal nerves. Subcutaneous injection of 50 microl saline into the nerve-injured paw induced a rapid and short-lasting increase in extracellular adenosine levels in the subcutaneous tissues of the rat hind paw ipsilateral to the nerve injury. Saline injection did not increase adenosine levels in sham-operated rats or non-treated rats. The adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine and the adenosine deaminase inhibitor 2'-deoxycoformycin, at doses producing a peripheral antinociceptive effect, did not further enhance subcutaneous adenosine levels in the nerve-injured paw. Systemic pretreatment with capsaicin, a neurotoxin selective for small-diameter sensory afferents, markedly reduced the saline-evoked release of adenosine in rat hind paw following spinal nerve ligation. Systemic pretreatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic afferent nerves, did not affect release. These results suggest that following nerve injury, peripheral capsaicin-sensitive primary sensory afferent nerve terminals are hypersensitive, and are able to release adenosine following a stimulus that does not normally evoke release in sham-operated or intact rats. Sympathetic postganglionic afferents do not appear to be involved in such release. The lack of effect on such release by the inhibitors of adenosine metabolism suggests an altered peripheral adenosine system following spinal nerve ligation.
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PMID:Enhanced release of adenosine in rat hind paw following spinal nerve ligation: involvement of capsaicin-sensitive sensory afferents. 1220 7

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
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PMID:Adenosine in the spinal cord and periphery: release and regulation of pain. 1278 73

Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A(1), A(2A), A(2B) and A(3). Adenosine plays an important role in many (patho)physiological conditions in the CNS as well as in peripheral organs and tissues. Adenosine receptors are present on virtually every cell. However, receptor subtype distribution and densities vary greatly. Adenosine itself is used as a therapeutic agent for the treatment of supraventricular paroxysmal tachycardia and arrhythmias and as a vasodilatatory agent in cardiac imaging. During the past 20 years, a number of selective agonists for A(1), A(2A) and A(3) adenosine receptors have been developed, all of them structurally derived from adenosine. Several such compounds are currently undergoing clinical trials for the treatment of cardiovascular diseases (A(1)and A(2A)), pain (A(1)), wound healing (A(2A)), diabetic foot ulcers (A(2A)), colorectal cancer (A(3)) and rheumatoid arthritis (A(3)). Clinical evaluation of some A(1) and A(2A) adenosine receptor agonists has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors; low brain penetration, which is important for the targeting of CNS diseases; short half-lifes of compounds; or a lack of effects, in some cases perhaps due to receptor desensitisation or to low receptor density in the targeted tissue. Partial agonists, inhibitors of adenosine metabolism (adenosine kinase and deaminase inhibitors) or allosteric activators of adenosine receptors may be advantageous for certain indications, as they may exhibit fewer side effects.
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PMID:Adenosine receptor agonists: from basic medicinal chemistry to clinical development. 1466 5

Adenosine kinase inhibition is an attractive therapeutic approach for several conditions for example, neurodegeneration, seizures, ischemia, inflammation and pain. Several nucleosidic and non-nucleosidic inhibitors are available. Using a virtual screening approach, we have discovered that 2-aryl oxazolo-pyrimidines are adenosine kinase inhibitors. Subsequent high throughput derivatization enabled the optimization of this new inhibitor chemotype resulting in highly potent derivatives. A variety of analogues were produced by applying liquid phase parallel synthesis to vary the 7-amino residues as well as the 2-aryl moiety.
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PMID:Discovery and optimization of 2-aryl oxazolo-pyrimidines as adenosine kinase inhibitors using liquid phase parallel synthesis. 1505 Jun 45

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