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, Oct 04, 2015
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    • "The A 2a receptor is expressed in various immune cells (i.e., neutrophils, macrophages, T cells, and natural killer cells) and its activation modulates cell trafficking, cell activity, viability and release of inflammatory mediators (Harada et al. 2000; Hasko et al. 2000; Chen et al. 2013). Moreover, a role for A 2a in the attenuation of inflammation and tissue damage has also been demonstrated in A 2a knockout mice (Ohta and Sitkovsky 2001). "
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    ABSTRACT: Although the anti-inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a-mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimization chemistry program with compound selection and profiling, multiple in vitro and in vivo assays were used, characterizing compound properties, pharmacodynamics (PD), and drug concentrations. Particularly, pharmacokinetic-PD modeling was applied to quantify the effects on the cardiovascular system, and an investigative toxicology study in rats was performed to explore potential myocardial toxicities. Compound 2, in comparison to a reference A2a agonist, UK-432,097, demonstrated higher solubility, lower lipophilicity, lower plasma protein binding, high rat lung retention (28% remaining after 24 h), and was efficacious in a lung inflammatory rat model following intratracheal dosing. Despite these properties, compound 2 did not provide a sufficient therapeutic index, that is, separation of local anti-inflammatory efficacy in the lung from systemic side effects in the cardiovascular system. The plasma concentration that resulted in induction of hypotension (half maximal effective concentration; EC50 0.5 nmol/L) correlated to the in vitro A2a potency (rIC50 0.6 nmol/L). Histopathological lesions in the heart were observed at a dose level which is threefold above the efficacious dose level in the inflammatory rat lung model. In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration. Despite its local anti-inflammatory efficacy in rat lung, small margins to the cardiovascular effects suggested limited therapeutic value of this compound for treatment of inflammatory lung disease by the inhaled route.
    06/2015; 3(3). DOI:10.1002/prp2.134
    • "Adenosine plays an essential role in the maintenance of brain homeostasis mainly acting through inhibitory adenosine A1 receptors and facilitatory adenosine A2A receptors (Fredholm et al., 2005). The parallel and combined effects mediated by A1 and A2A receptors control basal synaptic transmission and plasticity, respectively, and contribute to the encoding of salient information in neuronal circuits (Cunha, 2008), thus affecting different behaviours ranging from locomotion to mood (Chen et al., 2013). In particular, the participation of adenosine receptors in cognitive processes has been recognized over the years, as heralded by the ability of caffeine, a non-selective adenosine receptor antagonist, to control memory performance (reviewed in Cunha and Agostinho, 2010). "
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    ABSTRACT: Caffeine (a non-selective adenosine receptor antagonist) prevents memory deficits, an effect mimicked by adenosine A2A receptor (A2A R), but not A1 R, antagonists upon aging and Alzheimer's disease. We now tested if A2A R were also necessary for the emergence of memory impairment upon direct perturbation of the cholinergic system with scopolamine and if A2A R activation was sufficient to trigger memory deficits in naïve mice using 3 tests, to probe for short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze. The intra-peritoneal (i.p.) administration of scopolamine (1.0 mg/kg) impaired short-term memory performance in 3 tests, namely the object recognition task, inhibitory avoidance and modified Y-maze. In all these tests, scopolamine-induced amnesia was prevented by the A2A R (SCH 58261, 0.1-1.0 mg/kg, i.p.) as well as by A1 R antagonist (DPCPX, 0.2-5.0 mg/kg, i.p.) in all tests except the modified Y-maze, and both antagonists were devoid of effects on memory or locomotion in naïf rats. Notably, the activation of A2A R with CGS 21680 (0.1-0.5 mg/kg, i.p.) before the training session was sufficient to trigger memory impairment in the 3 tests in naïve mice, and effect prevented by SCH 58261 (1.0 mg/kg, i.p.). Furthermore, the intracerebroventricular administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task. These results show that A2A R are necessary and sufficient to trigger memory impairment and they further suggest that A1 R might also be selectively engaged to control the cholinergic-driven memory impairment. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; 172(15). DOI:10.1111/bph.13180 · 4.84 Impact Factor
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    • "Apart from a direct effect of ATP acting through P2X7R and P2Y1R , ATP may also impact on brain dysfunction upon its extracellular catabolism by ecto - nucleotidases ( Cunha , 2001 ; Zimmermann et al . , 2012 ) into adenosine , followed by activation of adenosine receptors ( Cunha , 2005 ; Chen et al . , 2007 , 2013 ; Gomes et al . , 2011 ) . In fact , there is robust evidence showing that the pharmacological or genetic deletion of adenosine A 2A receptors ( A 2A R ) diminishes neurodegeneration and brain dysfunction in animal models of aging ( Prediger et al . , 2005 ) , PD ( Schwarzschild et al . , 2006 ) , AD ( Canas et al . , 2009 ; Laurent et "
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    ABSTRACT: ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
    Frontiers in Neuroscience 04/2015; 9. DOI:10.3389/fnins.2015.00148 · 3.66 Impact Factor
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