Design and in Vivo Characterization of A₁ Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series

Abstract

N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A 1 adenosine receptor (A 1 AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A 1 AR compatibility. N 6 -Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A 1 AR) and known truncated N 6 -dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like.The pure diastereoisomer of known riboside 4 displayed high hA 1 AR selectivity. Methanocarba modification reduced A 1 AR selectivity of N 6 -dicyclopropylmethyl and endo-norbornyladenosines, but increased ribavirin selectivity. Most analogues tested (ip.) were inactive or weak in inducing mouse hypothermia, despite mA 1 AR full agonism and variable mA 3 AR efficacy, but

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Moreover, Cl-ENBA, a potent and highly selective A 1 AR agonist, amplified nociceptive thresholds in spinal glial, and microglial changes occurred in neuropathic pain [139]. MRS7469 also plays a role in pain relief or inhibition of lipolysis [140]. Further development of other agonists, such as SDZ WAG 994, GR79236, and GW-493838, as well as the allosteric enhancer T62, was discontinued [141].…”

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

“…Directly acting, potent agonists (1-15) and antagonists (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) for each of the ARs are available as pharmacological probes, and, in several cases, agents approved for human use ( Figure 2) [22]. AR agonists 1 (adenosine) and 9 (regadenoson) and are approved for clinical use in myocardial perfusion diagnostics and/or supraventricular tachycardia diagnosis and treatment.…”

“…In silico screening for binding at ARs, based on receptor X-ray structures, has identified numerous diverse chemotypes as candidate ligands, including some with known biological activity [124]. The antiviral drug ribavirin binds to the A 1 AR as a partial agonist [25].…”

“…Species are human (h), unless noted (m, mouse; r, rat). Values shown and for other compounds in Figure 2 are in Müller and Jacobson; Carlin et al; Wan et al; Tosh et al; Alnouri et al[22][23][24][25][26]. Values that represent >100-fold selectivity are shown in bold italics.…”

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

“…In silico screening for binding at ARs, based on receptor X-ray structures, has identified numerous diverse chemotypes as candidate ligands, including some with known biological activity (Rodríguez et al, 2016). The antiviral drug ribavirin binds to the A1AR as a partial agonist (Tosh et al, 2019).…”