Pharmacological and therapeutic effects of A3 adenosine receptor agonists

Fishman, Pnina; Bar-Yehuda, Sara; Liang, Bruce T.

doi:10.1016/j.drudis.2011.10.007

Cited by 208 publications

(236 citation statements)

References 70 publications

Supporting

Mentioning

225

Contrasting

Unclassified

Order By: Relevance

“…A role of the A3R was also excluded because the receptor is insensitive to DPCPX antagonism. 17 However, even though these findings indicated an exclusive involvement of brain A1R, to our surprise we found that Ado injected intraperitoneally or i.c.v. was less hypothermic than AMP (Figures 2A and 2B).…”

Section: Pharmacological Modulation Of Adenosine 5 0 -Monophosphatedecontrasting

confidence: 53%

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Muzzi

Blasi

Masi

et al. 2012

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5 0 -monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5 0 -nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5 0 -nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5 0 -monophosphate also suppresses prostaglandin E2-induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5 0 -nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness.

show abstract

Section: Pharmacological Modulation Of Adenosine 5 0 -Monophosphatedecontrasting

confidence: 53%

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Muzzi

Blasi

Masi

et al. 2012

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…MRS5698 includes multiple structural features that were optimized for potency and selectivity at the target A 3 AR, such as a [3.1.0]bicyclohexane ring system in place of ribose and a rigid extension at the C2 position. Several earlier A 3 agonists (ribosides IB-MECA (CF101), only 50-to100-fold selective in rat, and Cl-IB-MECA (CF102)) from our lab are currently in clinical trials for other indications (inflammatory diseases and cancer) [13]. MRS5698 displays higher affinity and selectivity (>3000-fold) vs. other ARs in both human and mouse, and both factors are consistent across species.…”

Section: Introductionmentioning

confidence: 94%

Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain

Tosh

Padia²,

Salvemini

et al. 2015

Purinergic Signalling

Self Cite

View full text Add to dashboard Cite

We reported that 2-(3,4-difluorophenylethynyl)-N 6 -3-chlorobenzyl (N)-methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A 3 adenosine receptors (A 3 ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A 3 AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from D-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma C max of 204 nM at 1 h with an AUC of 213 ng×h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.

show abstract

“…Blockade of adenosine A 2A receptor leads to inhibition of adenosinergic effects and inhibits immunosuppressive potential of T regs in tumor microenvironment [228]. Recently, it has been shown that adenosine receptor A 3 (A 3AR ) agonists have a protective action in various types of cancers (i.e., melanoma, prostate cancer, colon cancer, breast cancer, and hepatocellular carcinoma) through modulation of NF-κB and Wnt signaling pathways [229]. Adenosine A 3 receptor agonists have also inhibited the breast tumor-derived bone metastasis growth [230].…”

Section: Future Perspectivementioning

confidence: 99%

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Kumar

2012

Purinergic Signalling

View full text Add to dashboard Cite

Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs ), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy.

show abstract

Pharmacological and therapeutic effects of A3 adenosine receptor agonists

Cited by 208 publications

References 70 publications

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Contact Info

Product

Resources

About