793695-73-5Relevant academic research and scientific papers
(N)-methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists
Tchilibon, Susanna,Joshi, Bhalchandra V.,Kim, Soo-Kyung,Duong, Heng T.,Gao, Zhan-Guo,Jacobson, Kenneth A.
, p. 1745 - 1758 (2007/10/03)
A series of ring-constrained (N)-methanocarba-5′-uronamide 2,N 6-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5′-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5′-N-methylamide. The compounds, mainly 2-chloro-substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A3-AR agonists. Selected compounds were compared in binding to the rat A3AR to assess their viability for testing in rat disease models. The N 6-(3-chlorobenzyl) and N6-(3-bromobenzyl) analogues displayed Ki values at the human A3AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A3AR in comparison to the A1AR was the following (fold): the N6-(2,2-diphenylethyl) analogue 34 (1900), the N 6-(2,5-dimethoxybenzyl) analogue 26 (1200), the N6-(2,5- dichlorobenzyl) and N6-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N6-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A2A and A2BARs. The (N)-methanocarba-5′-uronamide analogues were full agonists at the A 3AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 μM. The N6-(2,2-diphenylethyl) derivative was an A3AR agonist in the (N)-methanocarba-5′- uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A3AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.
