P1 Receptor Agonists/Antagonists in Clinical Trials - Potential Drug Candidates of the Future

Abstract

Background: Adenosine mediates various physiological and pathological conditions by acting on its four P1 receptors (A1, A2A, A2B and A3 receptors). Omnipresence of P1 receptors and their activation, exert a wide range of biological activities. Thus, its modulation is implicated in various disorders like Parkinson’s disease, asthma, cardiovascular disorders, cancer etc. Hence these receptors have become an interesting target for the researchers to develop potential therapeutic agents. Number of molecules were designed and developed in the past few years and evaluated for their efficacy in various disease conditions. Objective: The main objective is to provide an overview of new chemical entities which have crossed preclinical studies and reached clinical trials stage following their current status and future prospective. Methods: In this review we discuss current status of the drug candidates which have undergone clinical trials and their prospects. Results: Many chemical entities targeting various subtypes of P1 receptors are patented; twenty of them have crossed preclinical studies and reached clinical trials stage. Two of them viz adenosine and regadenoson are approved by the Food and Drug Administration. Conclusion: This review is an attempt to highlight the current status, progress and probable future of P1 receptor ligands which are under clinical trials as promising novel therapeutic agents and the direction in which research should proceed with a view to come out with novel therapeutic agents.

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A2A Receptor-Mediated Effects in the Central Nervous System

“…In conclusion, the interaction between A 2A R and STEP (possibly through the involvement of mGlu 5 R) could have clinical relevance and its possible consequences should be contemplated when proposing drugs targeting the A 2A Rs. Notably, particular attention should be payed when considering A 2A R agonists as potential treatment for human pathologies (Borea et al, 2018;Borah et al, 2019), given their potential to impair cognitive performance by increasing STEP activity.…”

“…With the exception of the dorsal and ventral striatum, where A 2A R is present at remarkably high levels, in the rest of the brain the expression of the receptor is quite low (Rosin et al, 2003). Despite this, the huge importance of A 2A R in the CNS is witnessed by its role in the regulation of fundamental functions such as movement, cognition and emotions and, for this reason, it has attracted the interest of researchers as a potential therapeutic target (Borah et al, 2019). Indeed, the A 2A R antagonist istradefylline (Nourianz ® ) has recently been approved in the United States, after its first registration in Japan, for the treatment of Parkinson's disease, as an add-on to levodopa (Chen and Cunha, 2020).…”

Neonatal Seizures and Purinergic Signalling

“…With P1 receptors having a large role in cardiovascular and respiratory function via action upon the brainstem, the sudden rise of endogenous adenosine following seizures is hypothesised as one contributing factor to Sudden Unexpected Death in Epilepsy (SUDEP) [294]. Also, despite the documented use of many P1 receptor ligands reported in the literature, only adenosine and regadenoson (A2 A receptor antagonist) are approved for use in the clinic [295].…”

Pharmacological Tuning of Adenosine Signal Nuances Underlying Heart Failure With Preserved Ejection Fraction

“…Given this, adenosine-mediated signals have been implicated in many pathophysiological processes. Nowadays, adenosine receptor ligands are being extensively investigated as promising druggable compounds, some of which are undergoing clinical trials ( Borah et al, 2019 ). However, besides the native nucleoside, only a limited number of adenosine-related drugs are approved for clinical use ( Borah et al, 2019 ).…”