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.