Recent developments in adenosine receptor ligands and their potential as novel drugs

Müller, Christian; Jacobson, Kenneth A.

doi:10.1016/j.bbamem.2010.12.017

Cited by 395 publications

(480 citation statements)

References 181 publications

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“…The investigated AR agonists and antagonists can be structurally subdivided into several groups: (1) adenosine derivatives, (2) xanthine derivatives, and (3) nonnucleosidic adenine-like structures [46,47]. Among the compounds that showed anti-proliferative activity, members of all three structural classes were represented.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Schiedel

Lacher

Linnemann

et al. 2013

Purinergic Signalling

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The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutininstimulated human peripheral blood lymphocytes (PBL), and Jurkat T cells were investigated. Real-time PCR measurements confirmed the presence of all four AR subtypes on the investigated cells, although at different expression levels. A 2A ARs were predominantly expressed in PBL and further upregulated upon stimulation, while malignant Jurkat T cells showed high expression levels of A 1 , A 2A , and A 2B ARs. Cell proliferation was measured by [ 3 H]-thymidine incorporation assays. Several ligands, including the subtype-selective agonists CPA (A 1 ), BAY60-6583 (A 2B ), and IB-MECA (A 3 ), and the antagonists PSB-36 (A 1 ), MSX-2 (A 2A ), and PSB-10 (A 3 ) significantly inhibited cell proliferation at micromolar concentrations, which were about three orders of magnitude higher than their AR affinities. In contrast, further investigated AR ligands, including the agonists NECA (nonselective) and CGS21680 (A 2A ), and the antagonists preladenant (SCH-420814, A 2A ), PSB-1115 (A 2B ), and PSB-603 (A 2B ) showed no or only minor effects on lymphocyte proliferation. The anti-proliferative effects of the AR agonists could not be blocked by the corresponding antagonists. The non-selective AR antagonist caffeine stimulated phytohemagglutinin-activated PBL with an EC 50 value of 104 μM. This is the first study to compare a complete set of commonly used AR ligands for all subtypes on lymphocyte proliferation. Our results strongly suggest that these compounds induce an inhibition of lymphocyte proliferation and cell death through AR-independent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Schiedel

Lacher

Linnemann

et al. 2013

Purinergic Signalling

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“…An issue in the development of drugs acting on Ado receptors is that the receptors demonstrate an unusually high species dependence. In particular, the affinity of drugs is often different in rodents and human [341]. Therefore, the results of animal experimentation have to be carefully interpreted.…”

Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…messenger systems [6]. Pharmacological differences in terms of neutral antagonists and inverse agonists, however, have been determined [7].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Lu¹,

Wang²,

Zhang³

et al. 2014

Purinergic Signalling

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Potent and selective adenosine A 1 receptor (A 1 AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA 1 receptor, which was 217-fold more selective compared with hA 2A receptors and >1,000-fold selectivity for hA 1 over hA 3 receptor. The results obtained from [ 35 S]-GTPγS binding and cAMP concentration assays indicated that PQ-69 might be an A 1 AR antagonist with inverse agonist activity. In addition, PQ-69 displayed highly inhibitory activities on isolated guinea pig contraction (pA2 value of 8.99) induced by an A 1 AR agonist, 2-chloro-N6-cyclopentyl adenosine. Systemic administration of PQ-69 (0.03, 0.3, 3 mg/kg) increased urine flow and sodium excretion in normal rats. Furthermore, PQ-69 displayed better metabolic stability in vitro and longer terminal elimination half-life (t 1/2 ) in vivo compared with 1,3-dipropyl-8-cyclopentylxanthine. These findings suggest that PQ-69 exhibits potent antagonist effects on A 1 AR in vitro, ex vivo and in vivo, it might be a useful research tool for investigating A 1 AR function, and it could be developed as a potential therapeutic agent.

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Recent developments in adenosine receptor ligands and their potential as novel drugs

Cited by 395 publications

References 181 publications

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

The Antiepileptic Potential of Nucleosides

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

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