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

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 A(1), A(2A), A(2B) and A(3) adenosine receptors (ARs). In particular, A(1) 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 A(1) 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 A(1) AR agonists has been associated with numerous challenges like cardiovascular side effects, off-target activation as well as desensitization of A(1) AR leading to tachyphylaxis. In this regard, partial agonists of A(1) 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 A(1 )AR is found to be potent for the treatment of neuropathic pain, culminating the side effects related to off-target tissue activation of A(1) AR. This review provides an overview of the medicinal chemistry and therapeutic potential of various agonists/partial agonists, antagonists and allosteric modulators of A(1) AR, with a particular emphasis on their current status and future perspectives in clinical settings.