Search for New Purine- and Ribose-Modified Adenosine Analogs as Selective Agonists and Antagonists at Adenosine Receptors

Abstract

The binding affinities at rat A1, A2a, and A3 adenosine receptors of a wide range of derivatives of adenosine have been determined. Sites of modification include the purine moiety (1-, 3-, and 7-deaza; halo, alkyne, and amino substitutions at the 2- and 8-positions; and N6-CH2-ring, -hydrazino, and -hydroxylamino) and the ribose moiety (2'-, 3'-, and 5'-deoxy; 2'- and 3'- O-methyl; 2'-deoxy 2'-fluoro; 6'-thio; 5'-uronamide; carbocyclic; 4'- or 3'-methyl; and inversion of configuration). (-)- and (+)-5'-Noraristeromycin were 48- and 21-fold selective, respectively, for A2a vs A1 receptors. 2-Chloro-6'-thioadenosine displayed a Ki value of 20 nM at A2a receptors (15-fold selective vs A1). 2-Chloroadenin-9-yl(beta-L-2'-deoxy-6'- thiolyxofuranoside) displayed a Ki value of 8 microM at A1 receptors and appeared to be an antagonist, on the basis of the absence of a GTP-induced shift in binding vs a radiolabeled antagonist (8-cyclopentyl-1,3-dipropyl-xanthine). 2-Chloro-2'-deoxyadenosine and 2-chloroadenin-9-yl(beta-D-6'-thioarabinoside) were putative partial agonists at A1 receptors, with Ki values of 7.4 and 5.4 microM, respectively. The A2a selective agonist 2-(1-hexynyl)-5'-(N-ethylcarbamoyl)adenosine displayed a Ki value of 26 nM at A3 receptors. The 4'-methyl substitution of adenosine was poorly tolerated, yet when combined with other favorable modifications, potency was restored. Thus, N6-benzyl-4'-methyladenosine-5'-(N-methyluronamide) displayed a Ki value of 604 nM at A3 receptors and was 103- and 88-fold selective vs A1 and A2a receptors, respectively. This compound was a full agonist in the A3-mediated inhibition of adenylate cyclase in transfected CHO cells. The carbocyclic analogue of N6-(3-iodobenzyl)adenosine-5'-(N-methyluronamide) was 2-fold selective for A3 vs A1 receptors and was nearly inactive at A2a receptors.

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

“…As previously reported 14 and confirmed in this study, the SAR of adenosine agonists indicates that the ribose ring oxygen may be substituted with carbon; however, much affinity is lost. As with the N 6 -(3-iodobenzyl) aristeromycin derivative, 7b, simple carbocyclic substitution of the ribose moiety of otherwise potent N 6 -substituted adenosine agonists greatly diminishes affinity.…”

Induction of Apoptosis in HL-60 Human Promyelocytic Leukemia Cells by Adenosine A3Receptor Agonists

“…Since CADO (26,27) is equipotent to NECA at A 1 receptors (9.3 vs. 6.3 nM) and less potent than NECA at A 2a (63 vs. 10 nM), A 2b (24 vs. 2.6 μM), and A 3 (1890 vs. 113 nM) receptors, it is likely that the mechanism of apoptosis induced by CADO is not via adenosine receptors. Tanaka et al (4) observed an effect of ADO but not CADO on polyADP ribosylation activity in HL-60 cells, further supporting distinct mechanisms for cell death induced by these two analogues.…”

“…The hypothesis of a non-A 1 /A 2 receptor-mediated pathway for the action of CADO is further supported by our finding that an ADO A 1 /A 2 antagonist XAC had no effect on CADO-induced apoptosis in HL-60 cells. It is also noteworthy that a closely related compound, 2-chloro-2′-deoxyadenosine (cladribine), also induces apoptosis in leukemic cells (28), probably in an ADO receptor-independent fashion since it binds only very weakly to the receptors (26). Cladribine is currently being used in the treatment of leukemia (21).…”

The A3Adenosine Receptor: History and Perspectives

“…In an initial attempt, a large number of heterocyclic compounds were synthesized and evaluated as A 3 AR antagonists Siddiqi et al, 1995;Ji et al, 1996). In particular a triazoloquinazoline derivative 9-chloro-2-(2-furanyl)-5- [(phenylacetyl) (Kim et al, 1996).…”