Selective Ligands for Rat A3 Adenosine Receptors: Structure-Activity Relationships of 1,3-Dialkylxanthine 7-Riboside Derivatives

Abstract

1,3-Dibutylxanthine 7-riboside has been found to be a partial agonist at A3 adenosine receptors (van Galen et al. Mol. Pharmacol. 1994, 45, 1101-1111). 1,3-Dialkylxanthine 7-riboside analogues modified at the 1-, 3-, and 8-purine positions and at the ribose 5'-position were synthesized. The nucleoside analogues were examined for affinity in radioligand binding assays at rat brain A3 adenosine receptors stably expressed in CHO cells, using the radioligand [[125I]-4-amino-3-iodobenzyl]adenosine-5'-N-methyluronamide (AB-MECA). Affinity was assayed at rat brain A1 and A2a receptors using [3H]PIA and [3H]CGS 21680, respectively. The affinity of xanthine 7-ribosides at A3 receptors depended on the 1,3-dialkyl substituents in the order: Pent > or = Bu >> Hx > Pr approximately Me. 1,3-Dipentylxanthine 7-riboside was slightly selective for A3 receptors (2-fold vs A1 and 10-fold vs A2a). 8-Methoxy substitution was tolerated at A3 receptors. 2-Thio vs 2-oxo substitution increased potency at all three subtypes and slightly increased A3 vs A1 selectivity. The 5'-uronamide modification, which was previously found to enhance A3 selectivity in N6-benzyladenosine derivatives, was also incorporated into the xanthine 7-ribosides, with similar results. The affinity of 1,3-dialkylxanthine 7-riboside 5'-uronamides at A3 receptors depended on the N-alkyluronamide substituent in the order: MeNH > EtNH >> NH2 >> Me2N. Affinity of the 5'-uronamides at A3 receptors was dependent on the 1,3-dialkyl substitution in the order: Bu > Pent > Hex. 1,3-Dibutylxanthine 7-riboside 5'-N-methylcarboxamide, with a Ki value of 229 nM at A3 receptors, was 160-fold selective for rat A3 vs A1 receptors and > 400-fold selective vs A2a receptors. This derivative acted as a full agonist in the A3 receptor-mediated inhibition of adenylate cyclase.

Activation and desensitization of rat A3-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides

“…Displacement of binding of the radioligand [ 125 I]AB-MECA was monophasic, as indicated by Hill coefficients of approximately 1. As anticipated from previous binding experiments utilizing recombinant rat A 3 receptors Kim et al, 1994b], Cl-IB-MECA (K i = 4.9 nM) and I-AB-MECA (K i = 5.8 nM) were considerably more potent than DBXRM (K i = 0.60 μM) and DBXR (K i = 6.6 μM). K i values for 3′-deoxyDBXRM, 7c, were determined to be: 3.57 ± 0.99 at rat cortical A, receptors (vs. [ 3 H]R-PIA), 30.8 ± 4.3 at rat striatal A 2A receptors (vs. [ 3 H]CGS21680), and 37.6 ± 6.2 at recombinant rat A 3 receptors as described .…”

“…However, xanthine-7-ribosides have been explored as partial agonists at rat A 1 receptors [IJzerman et al, 1994] and in preliminary pharmacological characterization appeared to be either partial or full agonists at rat A 3 receptors [Kim et al, 1994b]. We synthesized a novel xanthine-7-riboside (7c) in an effort to reduce the efficacy of 7b, the removal of the 3′-hydroxyl group potentially leading to an A 3 receptor-selective antagonist.…”

“…We demonstrated that 1,3-dialkylxanthine-7-ribosides [Kim et al, 1994b] displayed greatly enhanced affinity compared to the parent xanthines at rat A 3 receptors. 1,3-Dibutylxanthine-7-riboside-5′-N-methylcarboxamide, DBXRM (7b, Fig.…”

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

“…Cl-IB-MECA has been described as a highly selective agonist for both human and rat A 3 adenosine receptors versus A 1 and A 2A receptors (Table 1) [32,35]. When Cl-IB-MECA and the A 3 antagonist MRS1523 were coapplied, the antagonist was always superfused 5 min before combining the two drugs.…”

Synthesis and purine receptor affinity of 6-oxopurine nucleosides and nucleotides containing (N)-methanocarba-pseudoribose rings

“…These 6-oxopurine bases were coupled at either the 7-(10-12) or 9-position (5-9) to the pseudoribose moiety, according to well-characterized alkylation patterns of purine bases. 7,12 A 5′-monophosphate derivative, 7a, and several 5′-triphosphate derivatives were included (9 and 12).…”