ArticleBMC pharmacology2011
Polyamidoamine (PAMAM) dendrimer conjugate specifically activates the A3 adenosine receptor to improve post-ischemic/reperfusion function in isolated mouse hearts.
Article in BMC pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 22 citations in OpenAlex.
- The cardiac toxicity of PAMAM dendrimer drug delivery systems can be attenuated with the adjunct use of cardioprotective agents.Biomolecules & biomedicine · 2025Article
- Mitigating Cardiotoxicity of Dendrimers: Angiotensin-(1-7) via Its Mas Receptor Ameliorates PAMAM-Induced Cardiac Dysfunction in the Isolated Mammalian Heart.Pharmaceutics · 2022Article
- Nanotoxicology of Dendrimers in the Mammalian Heart: ex vivo and in vivo Administration of G6 PAMAM Nanoparticles Impairs Recovery of Cardiac Function Following Ischemia-Reperfusion Injury.International journal of nanomedicine · 2020Article
- Ability of CP-532,903 to protect mouse hearts from ischemia/reperfusion injury is dependent on expression of ABiochemical pharmacology · 2019Article
- Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.Journal of controlled release : official journal of the Controlled Release Society · 2015Article
- Cardiac purinergic signalling in health and disease.Purinergic signalling · 2015Review
- Article
- Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates.Journal of medicinal chemistry · 2013Review
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Authors and funding
6 authors at 3 institutions in 1 country.
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Abstract
backgroundWhen stimulated by small molecular agonists, the A3 adenosine receptor (AR) mediates cardioprotective effects without inducing detrimental hemodynamic side effects. We have examined pharmacologically the protective properties of a multivalent dendrimeric conjugate of a nucleoside as a selective multivalent agonist for the mouse A3AR.
resultsA PAMAM dendrimer fully substituted by click chemistry on its peripheral groups with 64 moieties of a nucleoside agonist was shown to be potent and selective in binding to the mouse A3AR and effective in cardioprotection in an isolated mouse heart model of ischemia/reperfusion (I/R) injury. This conjugate MRS5246 and a structurally related model compound MRS5233 displayed binding Ki values of 0.04 and 3.94 nM, respectively, and were potent in in vitro functional assays to inhibit cAMP production. A methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose maintained a North conformation that is preferred at the A3AR. These analogues also contained a triazole linker along with 5'-N-methyl-carboxamido and 2-alkynyl substitution, previously shown to be associated with species-independent A3AR selectivity. Both MRS5233 and MRS5246 (1 and 10 nM) were effective at increasing functional recovery of isolated mouse hearts after 20 min ischemia followed by 45 min reperfusion. A statistically significant greater improvement in the left ventricular developed pressure (LVDP) by MRS5246 compared to MRS5233 occurred when the hearts were observed throughout reperfusion. Unliganded PAMAM dendrimer alone did not have any effect on functional recovery of isolated perfused mouse hearts. 10 nM MRS5246 did not improve functional recovery after I/R in hearts from A3AR gene "knock-out" (A3KO) mice compared to control, indicating the effects of MRS5246 were A3AR-specific.
conclusionsCovalent conjugation to a versatile drug carrier enhanced the functional potency and selectivity at the mouse A3AR and maintained the cardioprotective properties. Thus, this large molecular weight conjugate is not prevented from extravasation through the coronary microvasculature.
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