N⁶-Cyclopentyl-3‘-substituted-xylofuranosyladenosines:  A New Class of Non-Xanthine Adenosine A₁ Receptor Antagonists

Abstract

The present study explores the C-3' site of the 3-deoxy-3-xylofuranosyl ring of nucleoside analogues with an adenine or N6-cyclopentyladenine (CPA) base moiety and evaluates the effect on adenosine receptor affinity. Two series of sugar-modified adenosines, i.e., 3'-amido-3'-deoxyadenosines and 3'-amidated 3'-deoxyxylofuranosyladenines, were synthesized and tested for their affinity at A1 and A2a receptors in rat brain cortex and rat striatum, respectively. The modest affinity found in the "xylo series" prompted us to synthesize the corresponding N6-cyclopentyl derivatives, which proved to be well accommodated by the A1 receptors with potencies in the lower nanomolar range. This represents a new perspective in the purinergic field. The absence of a GTP-induced shift, i.e., the ratio between the affinities measured in the presence and absence of 1 mM GTP indicates an antagonistic behavior of this new class of CPA analogues.

Syntheses and Coordination Chemistry of Aminomethylphosphine Derivatives of Adenine

“…The proton signals of the dangling chain of La and 4a/6a are as easy to assign as their precursors 1aϪ3a, which will be reported elsewhere, with the triplet of (Table 1 and 2) to their precursors and other reported adenine analogues. [31] However, as revealed by a 1 H- 13 C heteronuclear correlation experiment, the 13 C signal of CH 2 NCH 2 PPh 2 is shifted to higher frequency between δ C ϭ 57.92 and 53.13 ppm and appears as a triplet or broad singlet due to coupling with the phosphorus atoms, while the signal of AdeCH 2 CH 2 remains as a singlet between δ C ϭ 42.58 and 41.69 ppm. The CH 2 PPh 2 signal, which appears as a doublet of doublets, doublet or broad singlet due to the 1 J P,C and/or 3 J P,C couplings, appears at the highest frequency in the alkyl region.…”

“…As shown by 31 P{ 1 H} NMR spectroscopy, however, there is always a trace of unidentified impurities (δ P ഠ 40.6, 37.7 and 36.5 ppm for sulfides; δ P ഠ 27.0 ppm for selenides) in the reaction mixture, implying that the PϪCϪN bond is not very robust under oxidation conditions. Attempts to get rid of the impurities were not successful by either chromatography or recrystallisation.…”

“…Monitoring by 31 P{ 1 H} NMR spectroscopy indicated that the reaction of 3a or 3b with a slight excess of Ph 2 PCH 2 OH (3: Ph 2 PCH 2 OH ഠ 1:2 molar ratio) gave La 3 CN gave the air-and moisturestable white solids L in good yields. The successful selectivity of NϪC bond formation at the dangling alkylamino group rather than the aryl C 6 ϪNH 2 at the purine ring can be attributed to the difference in basicities of the two primary amino groups.…”

“…All compounds have been fully characterised by microanalysis, IR, 1 H and 31 P{ 1 H} NMR spectroscopy, and EI/CI/FAB mass spectrometry. 1 H{ 31 P} NMR and 1 H- 13 C correlation experiments were used to confirm the spectral assignments where necessary. Two compounds were structurally characterised by X-ray crystallographic analysis.…”

Non‐Xanthine Antagonists for the Adenosine A1 Receptor

“…In 1988, Lohse et al published the properties of N 6 -cyclohexyl-2',3'-dideoxyadenosine 52, and showed it to possess antagonistic properties [94]. More significantly, Van Calenberg et al demonstrated nm affinity with ribose-modified compounds [95]. Cyclopentyl adenosine (CPA) was altered at the 3'-position with various amide derivatives.…”