Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

Abstract

Adenosine receptors (ARs) have been identified as promising therapeutic targets for countless pathological conditions, spanning from inflammatory diseases to central nervous system disorders, from cancer to metabolic diseases, from cardiovascular pathologies to respiratory diseases, and beyond. This extraordinary therapeutic potential is mainly due to the plurality of pathophysiological actions of adenosine and the ubiquitous expression of its receptors. This is, however, a double-edged sword that makes the clinical development of effective ligands with tolerable side effects difficult. Evidence of this is the low number of AR agonists or antagonists that have reached the market. An alternative approach is to target allosteric sites via allosteric modulators, compounds endowed with several advantages over orthosteric ligands. In addition to the typical advantages of allosteric modulators, those acting on ARs could benefit from the fact that adenosine levels are elevated in pathological tissues, thus potentially having negligible effects on normal tissues where adenosine levels are maintained low. Several A1 and various A3AR allosteric modulators have been identified so far, and some of them have been validated in different preclinical settings, achieving promising results. Less fruitful, instead, has been the discovery of A2A and A2BAR allosteric modulators, although the results obtained up to now are encouraging. Collectively, data in the literature suggests that allosteric modulators of ARs could represent valuable pharmacological tools, potentially able to overcome the limitations of orthosteric ligands.

A unified hypothesis of SUDEP: Seizure‐induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray

“…84,[100][101][102][103][104][105][106][107][108] Adenosine exerts its effects via interaction with four Gprotein-coupled receptors, which exert a number of effects on neurons, and drugs that act on these receptors have been developed. 109 Adenosine is known to exert significant inhibitory effects on respiration, and this action contributed importantly to the adenosine hypothesis of SUDEP. 41,49,97,108,[110][111][112][113] Adenosine is proposed to make a major contribution to postictal respiratory depression that occurs commonly after generalized seizures in animals 108 and in PWE.…”

“…In addition, greatly elevated levels of adenosine are produced by the breakdown of adenosine triphosphate, particularly during periods of high energy expenditure that occur during seizures, 99 which are detectable in plasma and the brain postictally 84,100–108 . Adenosine exerts its effects via interaction with four G‐protein‐coupled receptors, which exert a number of effects on neurons, and drugs that act on these receptors have been developed 109 . Adenosine is known to exert significant inhibitory effects on respiration, and this action contributed importantly to the adenosine hypothesis of SUDEP 41,49,97,108,110–113 .…”

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

“…Currently, Charite University is evaluating the efficacy, tolerability, and effects on HD biomarkers using an EGCG (daily dose of 1200 mg) supplement in a phase II clinical trial (NCT01357681). Further, T1-11 ( 52 ), isolated from Gastrodia elata , reduces the mHTT aggregation and protects against apoptotic cell death in HD [ 196 ]. Further, a combination of dextromethorphan (NMDA antagonist) and quinidine ( 53 ) is being evaluated in phase III clinical trial to mitigate the excitotoxicity in the HD brain (NCT03854019).…”

Investigation of adenosine A1 receptor-mediated β-arrestin 2 recruitment using a split-luciferase assay

“…ARs are divided into four subtypes, namely, A 1 AR, A 2A AR, A 2B AR, and A 3 AR. They are involved in many different physiological and pathological processes and gained high interest as pharmaceutical targets ( Sheth et al, 2014 ; Borea et al, 2018 ; Pasquini et al, 2022 ). ARs are expressed in several different cells, tissues, and major organs, including the brain, lungs, heart, liver, and kidney.…”