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A series of ring-constrained (N)-methanocarba-5‘-uronamide 2,N⁶-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 A3AR agonists. Selected compounds were compared in binding to the rat A3AR to assess their viability for testing in rat disease models. The N⁶-(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 N⁶-(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 A3AR, 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.

The hyperfine structure (hfs) and isotope shift (IS) in the isotopic chain of the radioactive element radon have been studied for the first time. The measurements were carried out by collinear fast-beam laser spectroscopy at the mass separator facility ISOLDE at CERN. The IS between 16 isotopes in the mass range 202≦A≦222 and the hfs of 7 odd-A isotopes were determined in the transitions 7s [3/2]2-7p [5/2]3 (745 nm) of Rn I. The nuclear spins and moments, as well as the observed inversion of the odd-even staggering for218–222Rn, can be associated with the effects of octupole instability around N=134.