Structure–activity relationships of adenosines with heterocyclic N 6-substituents

Abstract: Two series of N 6-substituted adenosines with monocyclic and bicyclic N 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 N 6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N 6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the A1AR; IC50 =3.2nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N 6-position was explored. N 6-(7-Azabicyclo[2.2.1]heptan-2-yl)adenosine (38) proved to be a reasonably potent A1 agonist (K i =51nM, IC50 =35nM) while further substitution on the 7″-nitrogen with tert-butoxycarbonyl (31, IC50 =2.5nM) and 2-bromobenzyloxycarbonyl (34, IC50 =9.0nM) gave highly potent A1AR agonists. [Copyright &y& Elsevier]