Structure–activity relationships of adenosines with heterocyclic N6-substituents

Two series of <i>N</i>⁶-substituted adenosines with monocyclic and bicyclic <i>N</i>⁶ substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([³H]CPX), potency, and intrinsic activity (cAMP accumulation) at the A₁ adenosine receptor in DDT₁ MF-2 cells. In the monocyclic series, the <i>N</i>⁶-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (<b>1</b> and <b>26</b>, respectively) were found to possess similar activities, whereas the corresponding selenium analogue <b>27</b> was found to be more potent. A series of nitrogen containing analogues showed varying properties, <i>N</i>⁶-((<i>3R</i>)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (<b>30</b>) was the most potent at the A₁AR; IC₅₀ = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the <i>N</i>⁶-position was explored. <i>N</i>⁶-(7-Azabicyclo[2.2.1]heptan-2-yl)adenosine (<b>38</b>) proved to be a reasonably potent A₁ agonist (K_i = 51 nM, IC₅₀ = 35 nM) while further substitution on the 7<i>″</i>-nitrogen with tert-butoxycarbonyl (<b>31</b>, IC₅₀ = 2.5 nM) and 2-bromobenzyloxycarbonyl (<b>34</b>, IC₅₀ = 9.0 nM) gave highly potent A₁AR agonists.<br />