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 A 3 AR agonists. Selected compounds were compared in binding to the rat A 3 AR to assess their viability for testing in rat disease models. The N 6 -(3-chlorobenzyl) and N 6 -(3-bromobenzyl) analogues displayed K i values at the human A 3 AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N 6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A 3 AR in comparison to the A 1 AR was (fold): the N 6 -(2,2-diphenylethyl) analogue 34 (1900), the N 6 -(2,5-dimethoxybenzyl) analogue 26 (1200), the N 6 -(2,5-dichlorobenzyl) and N 6 -(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N 6 -(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A 2A and A 2B ARs. The (N)-methanocarba-5′-uronamide analogues were full agonists at the A 3 AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 µM. The N 6 -(2,2-diphenylethyl) derivative was an A 3 AR 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 A 3 AR affinity in the 9-riboside series, including those that reducing intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.
We synthesized phenyl ring-substituted analogues of N 6 -(1S,2R)-(2-phenyl-1-cyclopropyl)adenosine, which is highly potent in binding to the human A 3 AR with a K i value of 0.63 nM. The effects of these structural changes on affinity at human and rat adenosine receptors and on intrinsic efficacy at the hA 3 AR were measured. A 3-nitrophenyl analogue was resolved chromatographically into pure diastereomers, which displayed 10-fold stereoselectivity in A 3 AR binding in favor of the 1S,2R isomer. A molecular model defined a hydrophobic region (Phe168) in the putative A 3 AR binding site around the phenyl moiety. A heteroaromatic group (3-thienyl) could substitute for the phenyl moiety with retention of high affinity of A 3 AR binding. Other related N 6 -substituted adenosine derivatives were included for comparison. Although the N 6 -(2-phenyl-1-cyclopropyl) derivatives were full A 3 AR agonists, several other derivatives had greatly reduced efficacy. N 6 -Cyclopropyladenosine was an A 3 AR antagonist, and adding either one or two phenyl rings at the 2-position of the cyclopropyl moiety restored efficacy. N 6 -(2,2-Diphenylethyl)adenosine was an A 3 AR antagonist, and either adding a bond between the two phenyl rings (N 6 -9-fluorenylmethyl) or shortening the ethyl moiety (N 6 -diphenylmethyl) restored efficacy. A QSAR study of the N 6 region provided a model that was complementary to the putative A 3 AR binding site in a rhodopsin-based homology model. Thus, a new series of highaffinity A 3 AR agonists and related nucleoside antagonists was explored through both empirical and theoretical approaches.
Abstract"Click chemistry" was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Binding affinity at the human A 1 , A 2A , and A 3 ARs (adenosine receptors) and relative efficacy at the A 3 AR were determined. Some triazol-1-yl analogues showed A 3 AR affinity in the low nanomolar range, a high ratio of A 3 /A 2A selectivity, and a moderate-to-high A 3 /A 1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A 3 AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A 3 AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A 3 AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A 1 AR and displaying a characteristic docking mode in an A 3 AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A 3 AR affinity and behaved as full agonists, i.e., 17, with 910-fold A 3 /A 1 selectivity. Thus, N 6 -substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleosidebased A 3 AR antagonists, partial agonists, and agonists.
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