Faculty Collaboration Database

Polyamidoamine (PAMAM) dendrimer conjugate specifically activates the A3 adenosine receptor to improve post-ischemic/reperfusion function in isolated mouse hearts. BMC Pharmacol 2011 Oct 31;11:11

Date

11/02/2011

Pubmed ID

22039965

Pubmed Central ID

PMC3247180

DOI

10.1186/1471-2210-11-11

Scopus ID

2-s2.0-80055018439 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

BACKGROUND: When 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.

RESULTS: A 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.

CONCLUSIONS: Covalent 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.

Author List

Wan TC, Tosh DK, Du L, Gizewski ET, Jacobson KA, Auchampach JA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine A3 Receptor Agonists
Animals
Binding, Competitive
Cyclic AMP
Dendrimers
Female
Mice
Mice, Knockout
Receptor, Adenosine A3
Reperfusion Injury