2,5‘-Disubstituted Adenosine Derivatives:  Evaluation of Selectivity and Efficacy for the Adenosine A₁, A_2A, and A₃ Receptor

Abstract

Novel 2,5'-disubstituted adenosine derivatives were synthesized in good overall yields starting from commercially available guanosine. Binding affinities were determined for rat adenosine A(1) and A(2A) receptors and human A(3) receptors. E(max) values were determined for the stimulation or inhibition of cAMP production in CHO cells expressing human adenosine A(2A) (EC(50) values as well) or A(3) receptors, respectively. The compounds displayed affinities in the nanomolar range for both the adenosine A(2A) and A(3) receptor, without substantial preference for either receptor. The derivatives with a 2-(1-hexynyl) group had the highest affinities for both receptors; compound 4 (2-(1-hexynyl)adenosine) had the highest affinity for the adenosine A(2A) receptor with a K(i) value of 6 nM (A(3)/A(2A) selectivity ratio of approximately 3), whereas compound 37 (2-(1-hexynyl)-5'-S-methyl-5'-thioadenosine) had the highest affinity for the adenosine A(3) receptor with a K(i) value of 15 nM (A(2A)/A(3) selectivity ratio of 4). In general, compounds with a relatively small 5'-S-alkyl-5'-thio substituent (methyl-5'-thio) displayed the highest affinities for both the adenosine A(2A) and A(3) receptor; the larger ones (n- or i-propyl-5'-thio) increased the selectivity for the adenosine A(3) receptor. The novel compounds were also evaluated in cAMP assays for their (partial) agonistic behavior. Overall, the disubstituted derivatives behaved as partial agonists for both the adenosine A(2A) and A(3) receptor. The compounds showed somewhat higher intrinsic activities on the adenosine A(2A) receptor than on the A(3) receptor. Compounds 37, 40 and 45, 48, with either a 5'-S-methyl-5'-thio or a 5'-S-i-propyl-5'-thio substituent had the lowest intrinsic activities on the adenosine A(2A) receptor. For the A(3) receptor, compounds 34, 35, 38, 39, and 46, 47, with a 5'-S-ethyl-5'-thio or a 5'-S-n-propyl-5'-thio substituent had the lowest intrinsic activities.

Partial Agonists for A3 Adenosine Receptors

“…A 5'-chloro-5'-deoxy substitution 26, already reported for adenosine agonists [24,10], greatly reduced A 3 AR efficacy. Modifications at the ribose moiety of adenosine resulted in a number of A 1 -selective compounds with reduced A 1 AR agonist activity.…”

“…The 2'-and 3'-hydroxy groups of adenosine and its derivatives are required for agonist activity and high affinity binding to the A 1 AR [26]. The respective 5'-modifications (including 5'-thioethers), in combination with N 6 -benzyl substituents known to increase A 3 AR affinity, resulted in partial agonists with high affinity at the human A 3 AR [17,10]. Increasing the size of the 5'-substituents reduced the efficacy at A 3 ARs [18,10].…”

“…In addition, partial agonists for A 1 ARs have clearly envisioned therapeutic applications. Isolated examples of partial agonists for A 2A ARs have been reported [9][10][11]. Hutchinson et al [12] reported that 2-iodo-N 6 -(2-S-endo-norborn-2-yl)adenosine 3 was a full agonist at the A 1 AR but have no detectable agonist activity at the A 2A AR.…”

Topological sub-structural molecular design (TOPS-MODE): a useful tool to explore key fragments of human $$\mathbf{A}_{3}$$ A 3 adenosine receptor ligands

“…Thus, a significant number of N6, C2, C8, and C5' adenosine derivatives were collected from the different literature sources [28][29][30][31][32][33][34][35]. The final values were reported as equilibrium inhibition constant (K i ) in nanomolar concentrations.…”

Semirational Design of (North)-Methanocarba Nucleosides as Dual Acting A1 and A3 Adenosine Receptor Agonists: Novel Prototypes for Cardioprotection

“…16 Some agonists of balanced potency have been reported; [17][18][19] however, they are often partial agonists and of selectivities limited to a particular species. The careful design and covalent joining of amine-functionalized congeners provide binary conjugates that are balanced in their ability to activate A 1 and A 3 ARs.…”