Adenosine receptor agonists: synthesis and binding affinity of 2- (aryl)alkylthioadenosine derivatives

The synthesis of a new series of 2-(aryl)alkylthio derivatives of N-ethylcarboxamido adenosine (NECA) is described, in comparison with the corresponding derivatives of adenosine. Binding studies (A1, A2A, and A3) and adenylyl cyclase activity (A2B) at human adenosine receptor subtypes stably transfected in Chinese hamster ovary (CHO) cells showed that the 2(aryl)alkylthioadenosine derivatives are more potent than the corresponding NECA derivatives at A1 receptors, while the NECA derivatives possess highest affinity at both A2A and A3 receptors. Thus, the 2-(1-pentyl)thioadenosine (7) with a Ki A1 = 91 nM, the 2-phenylethylthioNECA (18) with a Ki A2A = 24 nM, and the 2-phenylmethylthioadenosine (11) with a Ki A3 = 68 nM, could be useful tools to be modificated in order to find very potent and selective agonists for the human adenosine receptor subtypes.