Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

Abstract

Structural determinants of affinity of N6-substituted-5′-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N6-cycloalkyl and 3-halobenzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent dual acting human (h) A1AR agonist (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 11 and 26 were most potent at both h and rat (r) A3AR. All N6-substituted-5′-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hA3AR but agonists at the rA3AR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (A3AR antagonist blocked and A3AR agonist strongly potentiated). N6-Methyl-5′-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining A1AR and A3AR agonists. This study demonstrated for the first time the advantages of a single molecule activating two AR pathways both leading to benefit in this acute pain model.

Synthesis and evaluation of pharmacological activities of some 3-O-benzyl-4-C-(hydroxymethyl)-1,2-O-isopropylidene-α-D-ribofuranose derivatives as potential anti-inflammatory agents and analgesics

“…Nucleotide and nucleoside analogues synthesized from the α-D-ribofuranose sugar moiety have previously shown anti-nociceptive activity to some extent ( 10 ). Several nucleoside analogues had also demonstrated analgesic activity in a number of antinociceptive assays such as thermal nociception test ( 25 ), formalin induced paw screening assay ( 26 ) and the hot plate test ( 27 ).…”

“…Nucleotide and nucleoside analogues synthesized from the α-D-ribofuranose sugar moiety have previously shown potent antinociceptive activity without any side effects ( 10 ). Chemically modified small interfering RNAs (siRNAs) containing ribofuranose sugar moiety in the 3’-overhang region seemed to have increased nuclease resistance and knockdown effect generating great interest in the field of RNA interference-based therapeutics ( 11 ).…”

Adenosine Metabotropic Receptors in Chronic Pain Management

“…In fact, the selective pharmacological stimulation of the A 3 AR induced pronounced and prolonged antiallodynic effects in traumatic nerve-injury, chemotherapyinduced and other models of neuropathic pain (Bar-Yehuda et al, 2011;Chen et al, 2012;Fishman et al, 2012;Janes et al, 2015;Little et al, 2015;Tosh et al, 2015;Terayama et al, 2018;Wahlman et al, 2018;Stockstill et al, 2020). Moreover, A 3 ARselective agonists reduced the formalin-induced nocifensive behaviour and diabetic neuropathy (Yan et al, 2016;Petrelli et al, 2017). The A 3 AR seems to exert its beneficial effect at different levels of the pain axis.…”

Adenosine receptors as promising targets for the management of ocular diseases

“…Combining a 5′-C-ethyltetrazol-2-yl moiety with the appropriate N 6 -substitution in adenosine derivatives, an increased affinity versus both h A 1 AR and h A 3 AR (at the subnanomolar range) was achieved while remaining agonists at h A 1 AR and antagonists at h A 3 AR. The follow-up paper aimed to extend the series of 5′-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives, modifying the substituent in the N 6 -position of the adenine ring [ 137 ]. This study demonstrated for the first time that all dual-acting N 6 -substituted 5′‑C‑ethyl-tetrazolyl adenosine derivatives act as antagonists at human A 3 AR but as agonists at the rat A 3 AR, highlighting the importance of species differences for both affinity and efficacy at A 3 AR.…”