title: Anti-ischemic effects of multivalent dendrimeric A₃ adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart.
abstract: Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A₃ adenosine receptor (AR) agonists, chain-functionalized at the C2 or N⁶ position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A₁ and A₃ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A₃AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A₃AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A₃AR on the cardiomyocyte surface.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Chanyshev
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
authors.forename: Ahuva
authors.initials: A
authors.lastname: Isak
authors.forename: Alexandra
authors.initials: A
authors.lastname: Litinsky
authors.forename: Yelena
authors.initials: Y
authors.lastname: Chepurko
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Khai
authors.initials: K
authors.lastname: Phan
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry*; D006321:Heart / Q000187:drug effects*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043684:Receptor, Adenosine A3 / Q000378:metabolism
chemical_list: D058909:Adenosine A3 Receptor Agonists; D002316:Cardiotonic Agents; D050091:Dendrimers; C104700:PAMAM Starburst; D043684:Receptor, Adenosine A3; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide