Accumulating evidence supports a therapeutic role of purinergic signaling in cardiac diseases. Previously, efficacy of systemically infused MRS2339, a charged methanocarba derivative of 2-Cl-adenosine monophosphate, was demonstrated in animal models of heart failure. We now test the hypothesis that an uncharged adenine nucleoside phosphonate, suitable as an oral agent with a hydrolysis-resistant phospho moiety, can prevent the development of cardiac dysfunction in a post-infarction ischemic or pressure overload-induced heart failure model in mice. The diester-masked uncharged phosphonate MRS2978 was efficacious in preventing cardiac dysfunction with improved left ventricular (LV) fractional shortening when administered orally at the onset of ischemic or pressure overload-induced heart failure. MRS2925, the charged, unmasked MRS2978 analog, prevented heart dysfunction when infused subcutaneously but not by oral gavage. When administered orally or systemically, MRS2978 but not MRS2925 could also rescue established cardiac dysfunction in both ischemic and pressure overload heart failure models. The diester-masked phosphate MRS4074 was highly efficacious at preventing the development of dysfunction as well as in rescuing pressure overload-induced and ischemic heart failure. MRS2978 was orally bioavailable (57–75%) giving rise to MRS2925 as a minor metabolite in vivo, tested in rats. The data are consistent with a novel therapeutic role of adenine nucleoside phosphonates in systolic heart failure.
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High resolution mass spectrometry
Left anterior descending artery
Left ventricular posterior wall
Left ventricular end-diastolic diameter
Left ventricular end-systolic diameter
((1′R,2′R,3′S,4′R,5′S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)methyl diisopropyl phosphate
Transverse aorta constriction
Burnstock G (2017) Purinergic signalling: therapeutic developments. Front Pharmacol 8:661. https://doi.org/10.3389/fphar.2017.00661
Pijacka W, Moraes DJA, Ratcliffe LEK, Nightingale AK, Hart EC, da Silva MP, Machado BH, McBryde FD, Abdala AP, Ford AP, Paton JFR (2016) Purinergic receptors in the carotid body as a new drug target for controlling hypertension. Nat Med 22:1151–1159
Shen JB, Pappano AJ, Liang BT (2006) Extracellular ATP-stimulated current inwild-type and P2X4 receptor transgenic mouse ventricular myocytes: implications for a cardiac physiologic role of P2X4 receptors. FASEB J 20:277–284
Zhou SY, Mamdani M, Qanud K, Shen JB, Pappano A, Kumar TS, Jacobson KA, Hintze T, Recchia FA, Liang BT (2010) Treatment of heart failure by a methanocarba derivative of adenosine monophosphate. Implication for a role of cardiac P2X purinergic receptors. J Pharm Exp Therap 333:920–928
Kumar TS, Zhou SY, Joshi BV, Balasubramanian R, Yang T, Liang BT, Jacobson KA (2010) Structure activity relationship of (N)-methanocarba phosphonate analogues of 5′-AMP as cardioprotective agents acting through a cardiac P2X receptor. J Med Chem 53:2562–2576
Yang T, Shen JB, Yang R, Redden J, Dodge-Kafka K, Grady J, Jacobson KA, Liang BT (2014) Novel cardioprotective role of endogenous cardiac myocyte P2X4 receptors in heart failure. Circ Heart Fail 7:510–518
Jacobson KA, Ji X-d, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG (2000) Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem 43:2196–2203
Kim HS, Ravi RG, Marquez VE, Maddileti S, Wihlborg A-K, Erlinge D, Malmsjö M, Boyer JL, Harden TK, Jacobson KA (2002) Methanocarba modification of uracil and adenine nucleotides: high potency of northern ring conformation at P2Y1, P2Y2, P2Y4 and P2Y11, but not P2Y6 receptors. J Med Chem 45:208–218
Dunn PM, Kim HS, Jacobson KA, Burnstock G (2004) Northern ring conformation of methanocarba-adenosine 5′-triphosphate required for activation of P2X receptors. Drug Dev Res 61:227–232
Ravi RG, Kim HS, Servos J, Zimmermann H, Lee K, Maddileti S, Boyer JL, Harden TK, Jacobson KA (2002) Adenine nucleotides analogues locked in a northern methanocarba conformation: enhanced stability and potency as P2Y1 receptor agonists. J Med Chem 45:2090–2100
Pertusati F, Serpi M, McGuigan C (2012) Medicinal chemistry of nucleoside phosphonate prodrugs for antiviral therapy. Antivir Chem Chemother 22:181–203
Kumar TS, Yang T, Mishra S, Cronin C, Chakraborty S, Shen JB, Liang BT, Jacobson KA (2013) 5′-phosphate and 5′-phosphonate ester derivatives of (N)-methanocarba adenosine with in vivo cardioprotective activity. J Med Chem 56:902–914
Jones LR, Suzuki YJ, Kobayashi YM, Ramesh V, Franzini-Armstrong C, Cleemann L, Morad M (1998) Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin. J Clin Invest 101:1385–1393
Knollmann BC, Knollmann-Ritschel BEC, Weissmann NJ, Jones LR, Morad M (2000) Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. J Physiol 525:483–498
Sato Y, Ferguson DG, Sako H, Dorn GW II, Kadambi VJ, Yatani A, Hoit BD, Walsh RA, Kranias EG (1998) Cardiac-specific overexpression of mouse cardiac calsequestrin is associated with depressed cardiovascular function and hypertrophy in transgenic mice. J Biol Chem 273:28470–28477
Sonin D, Zhou SY, Cronin C, Sonina T, Wu J, Jacobson KA, Pappano A, Liang BT (2008) Role of P2X purinergic receptors in the rescue of ischemic heart failure. Am J Physiol Heart Circ Physiol 295:H1191–H1197
Tosh DK, Padia J, Salvemini D, Jacobson KA (2015) Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain. Purinergic Signal 11:371–387
Jansa P, Baszczyňski O, Procházková E, Dračínskýa M, Janeba Z (2012) Microwave-assisted hydrolysis of phosphonate diesters: an efficient protocol for the preparation of phosphonic acids. Green Chem 14:2282–2288
Tosh DK, Ciancetta A, Mannes P, Warnick E, Janowsky A, Eshleman AJ, Gizewski E, Brust TF, Bohn LM, Auchampach JA, Gao ZG, Jacobson KA (2018) Repurposing of a nucleoside scaffold from adenosine receptor agonists to opioid receptor antagonists. ACS Omega 3:12658–12678
Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang XP, Norval S, Sassano MF, Shin AI, Webster LA, Simeons FR, Stojanovski L, Prat A, Seidah NG, Constam DB, Bickerton GR, Read KD, Wetsel WC, Gilbert IH, Roth BL, Hopkins AL (2012) Automated design of ligands to polypharmacological profiles. Nature 492:215–220
Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA (2012) Pharmacological and therapeutic effects of A3 adenosine receptor (A3AR) agonists. Drug Disc Today 17:359–366
Hecker SJ, Erion MD (2008) Prodrugs of phosphates and phosphonates. J Med Chem 51:2328–2345
Toti KS, Derudas M, Pertusati F, Sinnaeve D, Van den Broeck F, Margamuljana L, Martins JC, Herdewijn P, Balzarini J, McGuigan C, Van Calenbergh S (2014) Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity. J Org Chem 79:5097–5112
KAJ received support from the NIDDK Intramural Research Program (ZIADK31127). This work was supported by the Calhoun Cardiology Research Endowment and HL48225 to BTL.
Conflicts of interest
Jian-Bing Shen declares that he has no conflict of interest.
Kiran S. Toti declares that he has no conflict of interest.
Saibal Chakraborty declares that he has no conflict of interest.
T. Santhosh Kumar declares that he has no conflict of interest.
Chunxia Cronin declares that she has no conflict of interest.
Bruce T. Liang declares that he has no conflict of interest.
Kenneth A. Jacobson declares that he has no conflict of interest.
This article does not contain any studies with human participants. The animal protocols were reviewed and approved by the Institutional Animal Ethics Committees at each institution where animal experiments were performed.
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Jian-Bing Shen and Kiran S. Toti are co-equal authors.
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Shen, J., Toti, K.S., Chakraborty, S. et al. Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives. Purinergic Signalling (2020). https://doi.org/10.1007/s11302-020-09688-0
- Purinergic receptors
- Adenine nucleoside phosphonate
- Cardiac function
- Heart failures