5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective A(1) adenosine receptor agonists: Affinity, efficacy, and selectivity for A(1) receptor from different species

A series of 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-C-methyl analogues of the A, adenosine receptor (AIAR) full agonists N-6-cyclopentyladenosine (CPA), 2-chloro-N-6-cyclopentyladenosine (CCPA), N-6-[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 N-6-cyclopentylamino series, the 5'-substituted derivatives showed a reduced affinity at the bovine A(1)AR compared to the parent compounds; however, the selectivity for A(1) versus A(2A) receptor was retained or increased. The corresponding N-6-3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine AIAR. The 5'-methylthionocarbamoyl derivative of 2'-Me-CCPA showed the best affinity at porcine AIAR with a K-i value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3- to 5-fold lower affinity at AIAR and very low affinity at the other subtypes (A(2A), A(2B), and A(3) compared to the corresponding N-6-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 A, agonists at the porcine receptor. Docking studies explained the lower affinity of N-6-3-(R)-tetrahydrofuranyl-substituted compounds at bovine AIAR compared to that of N-6-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-N-6-3-(R)-tetrahydrofuranyl adenosine analogues at human AIAR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7). (c) 2007 Elsevier Ltd. All rights reserved.