Functionalized Congeners of A₃ Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System

Abstract

(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A3 adenosine receptor (AR) agonists (5′-uronamides) or antagonists (5′-truncated). Here, these two series were modified in parallel at the adenine C2 position. N6-3-Chlorobenzyl-5′-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A3AR agonists. Flexibility of chain substitution allowed the conjugation with a fluorescent cyanine dye (Cy5) and biotin, resulting in binding Ki values of 17 and 36 nM, respectively. The distal end of the chain was predicted by homology modeling to bind at the A3AR extracellular regions. Corresponding l-nucleosides were nearly inactive in AR binding. In the 5′-truncated nucleoside series, 2-Cl analogues were more potent at A3AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (Ki = 2.1 nM) and truncated partial agonist 22 (Ki = 4.9 nM).

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“…These findings are comparable to previous findings with other GLiDe conjugates, which significantly improved affinity and potency over the unconjugated monomeric agonists [13,14,28]. The K i values of these agonists in binding to hARs have been reported and indicate that 3 , 5 , and 6 are all A 3 AR-selective [13,14,27]. For example, the triazole derivative 3 displayed K i values of 22.3 ± 1.6 nM and 2440 ± 320 nM at the hA 3 AR and hA 2A AR, respectively, and at 10 μM inhibited only 12 ± 4% of the radioligand binding at the hA 1 AR [13,14].…”

“…The conjugated MRS5246 was also 200-fold more potent A 3 AR agonist than the monomer, MRS5233, in an in vitro cAMP assay. These findings are comparable to previous findings with other GLiDe conjugates, which significantly improved affinity and potency over the unconjugated monomeric agonists [13,14,28]. The K i values of these agonists in binding to hARs have been reported and indicate that 3 , 5 , and 6 are all A 3 AR-selective [13,14,27].…”

“…The GLiDe conjugate MRS5246 was synthesized, as reported [13,14], by covalently conjugating a precursor monomer, MRS5221 5 , onto a fourth generation (G4) fully-substituted azido PAMAM dendrimer precursor 4b (Figure 1). The monomeric compound, MRS5233 3 , mimicked the structure of the modification of MRS5221 5 after conjugation to the dendrimer.…”

“…The K i values of these agonists in binding to hARs have been reported and indicate that 3 , 5 , and 6 are all A 3 AR-selective [13,14,27]. For example, the triazole derivative 3 displayed K i values of 22.3 ± 1.6 nM and 2440 ± 320 nM at the hA 3 AR and hA 2A AR, respectively, and at 10 μM inhibited only 12 ± 4% of the radioligand binding at the hA 1 AR [13,14]. Thus, the model compound 3 binds to the mA 3 AR with 5.7-fold greater affinity than to the hA 3 AR.…”

“…Adenosine agonists 3 , 5 , and 6 were synthesized as reported [13,14]. Adenosine agonists were first dissolved in DMSO and stored at -20 °C as stock solutions.…”