Design and Synthesis of Truncated 4'-Thioadenosine Derivatives as Potent and Selective A3 Adenosine Receptor Antagonists

Abstract

We have established structure-activity relationships of novel truncated D-4′-thioadenosine derivatives from D-mannose as potent and selective A 3 adenosine receptor (AR) antagonists. At the human A 3 AR, most of N 6 -substituted analogues showed high potency and selectivity and acted as pure antagonists in a cyclic AMP functional assay. Among compounds tested, 2-chloro-N 6 -3-chlorobenzyl and N 6 -3-chlorobenzyl analogues displayed very high binding affinities (K i = 1.66 nM and 1.5 nM, respectively) at the human A 3 AR. Truncated 4′-thioadenosine derivatives studied here are regarded as an excellent template for the design of novel A 3 AR antagonists to act at both human and murine species.

Medicinal Chemistry of A3 Adenosine Receptor Modulators: Pharmacological Activities and Therapeutic Implications

“…Compounds 83 and 84 also demonstrated high affinity at the rA 3 AR expressed in CHO cells ( K i of 6.2 and 3.9 nM, respectively), indicating the possibility of evaluation in small animal models for future drug development, and were inactive as agonists or antagonists in a cyclic AMP functional assay at the hA 2B AR. The removal of the 2-Cl atom did not affect hA 3 R affinity while significantly reducing selectivity versus the remaining AR subtypes. , The l -enantiomers of 4′-thioadenosines were shown to be totally devoid of AR affinity . A recent series of 4′-oxo bioisosters of 84 were shown to be generally less potent than the corresponding 4′-thio nucleosides although still exerting considerable potency both as human and rat AR antagonists (see compound 85 ) .…”

“…The removal of the 2-Cl atom did not affect hA 3 R affinity while significantly reducing selectivity versus the remaining AR subtypes. 113,114 The L-enantiomers of 4′-thioadenosines were shown to be totally devoid of AR affinity. 114 A recent series of 4′-oxo bioisosters of 84 were shown to be generally less potent than the corresponding 4′-thio nucleosides although still exerting considerable potency both as human and rat AR antagonists (see compound 85).…”

In vitro effect of adenosine on the mRNA expression of Kir 2.1 and Kir 4.1 channels in rat retinal Müller cells at elevated hydrostatic pressure

“…Adenosine is a natural chemical messenger, which binds to four subtypes (A 1 , A 2A , A 2B and A 3 ) of adenosine receptors (ARs), and regulates the physiological functions of cells. In the retina, adenosine is capable of dilating vessels and serves an autoregulatory role in mediating the compensatory dilation in response to hypoxia, ischemia, hypoglycemia and high hydrostatic pressure (13)(14)(15) (16,17).…”

In vitro effect of adenosine A2A receptor antagonist SCH 442416 on the expression of glutamine synthetase and glutamate aspartate transporter in rat retinal M�ller cells at elevated hydrostatic pressure

“…Adenosine, is a natural chemical messenger binding to four subtypes (A 1 , A 2A , A 2B , A 3 ) of adenosine receptors (ARs) and regulates physiological functions of the cell (18). It has been shown that adenosine receptors were expressed in the rat eye.…”