Structure-Based Design, Synthesis, and In Vivo Antinociceptive Effects of Selective A₁ Adenosine Receptor Agonists

Abstract

Our previous work discovered that combining the appropriate 5'- and N-substitution in adenosine derivatives leads to the highly selective human A adenosine receptor (hAAR) agonists or highly potent dual hAAR agonists and hAAR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N-substituted-5'-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The N-(±)-endo-norbornyl derivative 12 was the most potent and selective at AAR and effective as an analgesic in formalin test in mice, but none of the 5'-pyrazolyl series compounds showed a dual behavior at hA and hAAR. Molecular modeling studies rationalized the structure-activity relationships and the selectivity profiles of the new series of AAR agonists. Interestingly, an unexpected inverted binding mode of the N-tetrahydrofuranyl derivative 14 was hypothesized to explain its low affinity at AAR.

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels

“…105 Moreover, adenosinergic signalling is known to modulate intestinal functionality. [2][3][4] For decades, it was thought that the analgesic effects of adenosine were mediated by A 1 adenosine receptor (A 1 AR) activation, 8,54,65,77,105 but research efforts over the past several years have also implicated a key role for the A 3 AR subtype. 43,75 For example, A 3 AR agonists are able to block the development of trauma-and chemotherapeutic-induced neuropathic pain 17,42 and are also effective in reducing inflammatory and cancer-related pain.…”

Synthesis of Ribavirin, Tecadenoson, and Cladribine by Enzymatic Transglycosylation

“…To date, the only synthetic strategy to obtain Tecadenoson (2) consists of nucleophilic substitution on either 2 ,3 ,5 -tri-O-acetyl-6-chloroinosine or 6-chloroinosine with (R)-3-aminotetrahydrofurane or its salts followed, when necessary, by deprotection with ammonia (reported yield: 68%) [34][35][36].…”

“…In this context, we explored the use of 7-methylguanine arabinoside iodide (9) (Scheme 1) as the sugar donor for the synthesis of arabinosyl purine analogues such as the antiviral drug Vidarabine, as an alternative scheme to both the conventional chemical synthesis and the bi-enzymatic transglycosylation reaction [6]. aminotetrahydrofurane or its salts followed, when necessary, by deprotection with ammonia (reported yield: 68%) [34][35][36].…”

Adenosine receptors as promising targets for the management of ocular diseases

“…Adenosine is the primary endogenous agonist of the A 1 AR, whereas countless A 1 AR agonists with every disparate modification at ribose moiety and the adenine N 6 and C2 positions have been disclosed in the last two decades [33][34][35][36][37][38][39][40]. Before the discovery of the A 3 subtype, several agonists have been identified as selective for A 1 AR (Fig.…”

“…To date, the A 3 AR antagonists tested for their effects on lowering IOP consisted of: the 6-phenyl-1,4-dihydropyridine derivatives MRS-1097 (32, Fig. 12) and MRS-1191 (33), the nonxanthine heterocyclic derivative MRS-1220 (34), the pyridine derivative MRS 1523 (35), the nucleoside-based antagonists MRS-1292 (36), MRS-3771 (37), MRS3826 (38), LJ-979 (39), and LJ-1251 (40), the triazolopurine derivative OT-7999 (41), PBF-677 (structure not disclosed), and ACN-1052 (structure not disclosed).…”