5′-Carbamoyl derivatives of 2′-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: Affinity, efficacy, and selectivity for A1 receptor from different species

A series of 5′-carbamoyl and 5′-thionocarbamoyl derivatives of 2′-C-methyl analogues of the A1 adenosine receptor (A1AR) full agonists N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), N6-[3-(R)-tetrahydrofuranyl]adenosine (tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized and evaluated for their affinity for adenosine receptor subtypes from bovine, porcine, and human species. In the N6-cyclopentylamino series, the 5′-substituted derivatives showed a reduced affinity at the bovine A1AR compared to the parent compounds; however, the selectivity for A1 versus A2A receptor was retained or increased. The corresponding N6-3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine A1AR. The 5′-methylthionocarbamoyl derivative of 2′-Me-CCPA showed the best affinity at porcine A1AR with a Ki value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3- to 5-fold lower affinity at A1AR and very low affinity at the other subtypes (A2A, A2B, and A3) compared to the corresponding N6-cyclopentyl analogues. The 5′-carbamoyl and 5′-thionocarbamoyl derivatives of 2′-Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were found to be partial A1 agonists at the porcine receptor. Docking studies explained the lower affinity of N6-3-(R)-tetrahydrofuranyl-substituted compounds at bovine A1AR compared to that of N6-cyclopentyl analogues, showing that the oxygen of the tetrahydrofuranyl ring establishes unfavorable electrostatic interactions with the CO oxygen of Asn254. The low binding affinity of the 2′-C-methyl-N6-3-(R)-tetrahydrofuranyl adenosine analogues at human A1AR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7).