2-Chloro-N6-cyclopentyladenosine: a highly selective agonist at A1 adenosine receptors

Summary 2-Chloro-N⁶-cyclopentyladenosine (CCPA) was synthesized as a potential high affinity ligand for A₁ adenosine receptors. Binding of [³H]PIA to A₁ receptors of rat brain membranes was inhibited by CCPA with a K_i-value of 0.4 nM, compared to a K_i-value of 0.8 nM for the parent compound N⁶-cyclopentyladenosine (CPA). Binding of [³H]NECA to A₂ receptors of rat striatal membranes was inhibited with a K_i-value of 3900 nM, demonstrating an almost 10,000-fold A₁-selectivity of CCPA.CCPA inhibited the activity of rat fat cell membrane adenylate cyclase, a model for the A₁ receptor, with an IC₅₀-value of 33 nM, and it stimulated the adenylate cyclase activity of human platelet membranes with an EC₅₀-value of 3500 nM. The more than 100-fold A₁-selectivity compares favourably with a 38-fold selectivity of CPA. Thus, CCPA is an agonist at A₁ adenosine receptors with a 4-fold higher selectivity and 2-fold higher affinity than CPA, and a considerably higher selectivity than the standard A₁ receptor agonist R-N⁶-phenylisopropyladenosine (R-PIA). CCPA represents the agonist with the highest selectivity for A₁ receptors reported so far.Abbreviations CCPA 2-choro-N⁶-cyclopentyladenosine - CPA N⁶-cyclopentyladenosine - NECA 5-N-ethylcarboxamidoadenosine - PIA N⁶-phenylisopropyladenosineSend offprint requests to M. J. Lohse at the above address