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Synthesis and Biological Evaluation of Adenosines with Heterobicyclic and Polycyclic N6-Substituents as Adenosine A1 Receptor Agonists

Authors

  • Joshua I. Gosling,

    1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia)
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  • Prof. Stephen P. Baker,

    1. Department of Pharmacology & Therapeutics, University of Florida College of Medicine, P.O. Box 100267, Gainesville, FL 32610 (USA)
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  • Dr. John M. Haynes,

    1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052 (Australia)
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  • Prof. Michael Kassiou,

    1. Brain and Mind Research Institute, 100 Mallett Street, Camperdown, NSW 2050 (Australia)
    2. School of Chemistry, University of Sydney, Sydney, NSW 2006 (Australia)
    3. Discipline of Medical Radiation Sciences, University of Sydney, Sydney, NSW 2006 (Australia)
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  • Prof. Colin W. Pouton,

    1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052 (Australia)
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  • Lyndon Warfe,

    1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052 (Australia)
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  • Dr. Paul J. White,

    1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville VIC 3052 (Australia)
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  • Prof. Peter J. Scammells

    Corresponding author
    1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia)
    • Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 (Australia)
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Abstract

A concise synthesis of a series of N6-substituted adenosines with bicyclo[3.2.1]octan-6-yl and polycyclic N6-substituents has been developed. The adenosine A1 receptor (A1R) affinity and potency of these compounds was initially assessed using competitive binding assays and cyclic adenosine monophosphate (cAMP) accumulation assays in DDT1 MF-2 cells. The potency and receptor subtype selectivity of selected examples was further evaluated by measuring their effects on cAMP accumulation at all human adenosine receptor subtypes expressed in CHO cells. The results of these assays indicated that all of the synthesised N6-substituted adenosines are full agonists at A1R and activate this receptor selectively over the other adenosine receptor subtypes. The two standout compounds in terms of potency were N6-(3-thiabicyclo[3.2.1]octan-6-yl)adenosine and N6-(cubanylmethyl)adenosine with EC50 values at human A1R of 2.3 nM and 1.1 nM, respectively. The cubanylmethyl derivative in particular proved to be highly receptor subtype selective. These two compounds were further evaluated in a simulated ischaemia model in cultured cardiomyoblasts, where they were found to impart protective effects under hypoxic conditions that resulted in a significant reduction in cell death.

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