Affinity and selectivity of tecadenoson, 2-chloro-tecadenoson and 2’-C-methyl analogues at bovine and pig A1 adenosine receptor

Adenosine A1 receptor agonists have a great interest as neuroprotective agents for the treatment of glutamate-related neurodegenerative disorders and as antilipolytic agents. Moreover, A1 agonists have received particular attention for their therapeutic potential as anti-arrhythmic agents. Thus, a number of adenosine derivatives as selective A1 agonists have been developed. Tecadenoson (CVT510, N6-3-®-tetrahydrofuranyl-adenosine) a potent and selective A1 full agonist, is in clinical trials for treatment of supra ventricular tachyarrythmias and for slowing of ventricular rate during atrial fibrillation. Recently, we disclosed 2'-Me-CCPA (2-chloro-2'-C-methyl-N6-cyclopentyl-adenosine) as a potent and very selective agonist at bovine and human A1 adenosine receptor. Thus, as an extension of our previous work on adenosine derivatives with high affinity and selectivity toward A1 receptor, we became interested in the preparation of Tecadenoson analogues substituted in position 2 of the purine ring with a chlorine atom and/or in position 2' of the ribose with a methyl group. In binding studies at A1 bovine cortical membranes, tecadenoson, 2'-C-methyl-tecadenoson, 2-chloro-Tecadenoson and 2-chloro-2'-C-methyl-tecadenoson showed significantly reduced affinity as compared to that at the corresponding pig receptor. On the contrary, CPA, CCPA, and 2'-Me-CCPA showed higher affinity at bovine A1 receptor. The lower affinity of Tecadenoson and its analogues at bovine A1 receptor could be explained in terms of reduced ability of the N6-(3-(R)-tetrahydrofuranyl)-substitutted adenosine analogues to trigger a productive interaction with a number of aminoacids that are involved in the binding of the corresponding N6-cyclopentyl substituted derivatives, as pointed out by molecular modeling studies.