Medicinal Chemistry and Therapeutic Potential of Agonists, Antagonists and Allosteric Modulators of A1 Adenosine Receptor: Current Status and Perspectives

Abstract

Adenosine is a purine nucleoside, responsible for the regulation of a wide range of physiological and pathophysiological conditions by binding with four G-protein-coupled receptors (GPCRs), namely A1, A2A, A2B and A3 adenosine receptors (ARs). In particular, A1 AR is ubiquitously present, mediating a variety of physiological processes throughout the body, thus represents a promising drug target for the management of various pathological conditions. Agonists of A1 AR are found to be useful for the treatment of atrial arrhythmia, angina, type-2 diabetes, glaucoma, neuropathic pain, epilepsy, depression and Huntington’s disease, whereas antagonists are being investigated for the treatment of diuresis, congestive heart failure, asthma, COPD, anxiety and dementia. However, treatment with full A1 AR agonists has been associated with numerous challenges like cardiovascular side effects, off-target activation as well as desensitization of A1 AR leading to tachyphylaxis. In this regard, partial agonists of A1 AR have been found to be beneficial in enhancing insulin sensitivity and subsequently reducing blood glucose level, while avoiding severe CVS side effects and tachyphylaxis. Allosteric enhancer of A1 AR is found to be potent for the treatment of neuropathic pain, culminating the side effects related to off-target tissue activation of A1 AR. This review provides an overview of the medicinal chemistry and therapeutic potential of various agonists/partial agonists, antagonists and allosteric modulators of A1 AR, with a particular emphasis on their current status and future perspectives in clinical settings.

Accuracy and Precision of the Receptorial Responsiveness Method (RRM) in the Quantification of A1 Adenosine Receptor Agonists

“…Receptor desensitization is a general mechanism that affects every receptor, including the adenosine receptor family [16,17,27]. This phenomenon is of special significance regarding the A 1 adenosine receptor, as any alteration in its responsiveness might modify vital protective and regenerative processes throughout the body [16,28].…”

“…NECA, CPA, and CHA were decided as agonists to construct the E/c curves to be fitted in the present work. NECA stimulates both the A 1 and A 2 adenosine receptors, while CPA and CHA are highly selective for the A 1 adenosine receptor [16,27], the predominant adenosine receptor type of the myocardium [16,24]. These synthetic compounds are less sensitive to adenosine-handling enzymes and carriers than adenosine, the endogenous agonist of the adenosine receptor family [16,26], so E/c curves of these synthetic agonists are more suitable for quantitative evaluation than those of adenosine.…”

Ectonucleotidases in Acute and Chronic Inflammation

“…On the whole, these findings indicate a relationship between NTPDase1/CD39 expression on both Treg and CD4 + IL-17 + cells and hyper-glycemia, overweight and obesity ( Cortez-Espinosa et al, 2015 ). Finally, it is an established fact that adenosine receptor blockade reverses insulin resistance in skeletal muscle from diabetic rats ( Challis et al, 1984 ), and pharmacological manipulation of the adenosinergic system is proposed as an approach to manage T2D and associated complications ( Antonioli et al, 2015 ; Deb et al, 2019 ).…”

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

“…Neladenoson bialanate (BAY 1067197; 3; Figure 1) is currently in clinical evaluation for the treatment of chronic heart failure with preserved/reduced ejection fraction (HFpEF and HFrEF, respectively) [50][51][52][53][54][55][56][57]. Early results show a lack of dose-dependent favorable effects on cardiac structure and function and on exercise capacity, with a dose-dependent decrease in renal function [58,59].…”