Adenosine receptors as drug targets—What are the challenges?

Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 03/2013; 12(4):265-286. DOI: 10.1038/nrd3955
Source: PubMed


Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors - either directly or indirectly - have now entered the clinic. However, only one adenosine receptor-specific agent - the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) - has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.

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Available from: Bertil B Fredholm
    • "* * Corresponding author . research groups have extensively investigated the pyrazolo[4,3-e] [1] [2] [4]triazolo[1,5-c]pyrimidine ( PTP ) nucleus as basis for the design of ARs antagonists [ 12e23] . Through the modulation of the substitution pattern at the C5 ( C5 PTP ) and N7 ( N7 PTP ) positions , potent and selective human ( h ) A 2A AR and A 3 AR antagonists ( compounds A [ 15 ] and B [ 18 ] , Chart 1 ) were reported . "
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    ABSTRACT: The structure-activity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 = 94.6 nM; KihA2A = 1.11 nM; IC50hA2B = 2214 nM; KihA3 = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki = 1.44 nM; hA1/hA2A = 216.0; hA3/hA2A = 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR.
    No preview · Article · Jan 2016 · European Journal of Medicinal Chemistry
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    • "Adenosine acts at four distinct extracellular G-proteincoupled receptors (A 1 R, A 2A R, A 2B R, A 3 R) as an endogenous signaling agent, and participates in physiological, non-physiological (perturbed) and pathological (diseased, dysfunctional) states. It can regulate diverse functions such as cardiovascular, respiratory and renal function, inflammatory and immune events, and CNS events, and there has been considerable interest in developing adenosine-based therapeutics for conditions involving these systems (Jacobson and Gao, 2006; Schenone et al., 2010; Gessi et al., 2011; Chen et al., 2013). A role for adenosine in antinociception was first identified in the 1970s and then elaborated in the 1980s with systemic and spinal (intrathecal, or i.t.) administration of selective agonists. "
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    ABSTRACT: The main focus for development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signalling and may be useful for inflammatory and neuropathic pain. A2BR agonists exhibit peripheral proinflammatory effects on immune cells, but also spinal antinociceptive effects similar to A2AR agonists. A3Rs are now demonstrated to produce antinociception in several preclinical neuropathic pain models, with mechanistic actions on glial cells, and may be useful for neuropathic pain. Endogenous adenosine levels can be augmented by inhibition of metabolism (via adenosine kinase) or increased generation (via nucleotidases), and these approaches have implications for pain. Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating efficacy of adenosine-based analgesics.
    Full-text · Article · Oct 2015 · Neuroscience
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    • "Adenosine e an epigenetic mediator of KD therapy The purine ribonucleoside adenosine is a well-recognized endogenous anticonvulsant and seizure terminator (Dunwiddie, 1980). Its anticonvulsant effects are largely based on activation of presynaptic G-protein coupled adenosine A 1 receptors (A 1 R), which provide presynaptic inhibition of glutamate release, and by activation of postsynaptic A 1 Rs, which stabilize the postsynaptic membrane potential by promoting G-protein coupled inwardly rectifying potassium currents (Chen et al., 2013). Our data showing increased hippocampal adenosine (Fig. 4A) and seizure suppression during KD treatment (Fig. 3B) are consistent with the A 1 R-dependent mechanism of seizure suppression. "
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    ABSTRACT: Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Aug 2015 · Neuropharmacology
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