Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

Abstract

Potent and selective adenosine receptor (AR) agonists are of pharmacological interest for the treatment of a wide range of diseases and conditions. Among these derivatives, nucleoside-based agonists represent the great majority of molecules developed and reported to date. However, the limited availability of compounds selective for a specific AR subtype (i.e., A2BAR) and a generally long and complex synthetic route for largely substituted nucleosides are the main drawbacks of this category of molecules. Non-nucleoside agonists represent an alternative set of compounds able to stimulate the AR function and based on simplified structures. This review provides an updated overview on the structural classes of non-nucleoside AR agonists and their biological activities, with emphasis on the main derivatives reported in the literature. A focus is also given to the synthetic routes employed to develop these derivatives and on molecular modeling studies simulating their interaction with ARs.

Adenosine receptors as promising targets for the management of ocular diseases

“…As a consequence of the crucial involvement of A l agonists in heart rate and blood pressure regulation, the therapy for glaucoma or ocular hypertension built on A l AR agonists suffers from significant limitations [ 53 ]. For this reason, several non-nucleoside A 1 AR partial agonists have been developed [ 54 ]. The rationale for using A 1 AR partial agonists is based on avoiding receptor desensitization and on achieving a specific tissue selectivity of the effects without generating drawbacks [ 55 , 56 ].…”

Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease

“…ARs (A 1 R, A 2A R, A 2B R and A 3 R) are GPCRs stimulated by endogenous adenosine, involved in several physiological and pathological processes [76]. The stimulation of A 1 R and A 3 R by adenosine leads to the activation inhibiting G (G i/o ) proteins with the consequent inhibition of adenylate cyclase and intracellular reduction of cyclic adenosine monophosphate (cAMP).…”

“…Instead, A 2A R and A 2B R promote the G protein activation and the subsequent increase of cAMP [77]. ARs activation involves the modulation of second messengers and additional signaling mechanisms such as phospholipase C; the protein kinase C dependent on Ca 2+ involved in cell communication; phosphoinositide 3-kinases/protein kinase B (PI 3 K/Akt) signaling involved in cell proliferation, growth and differentiation; and the activation of ion channels and regulation of Ca 2+ [76,78]. ARs are located in immune cells, blood vessels, astrocytes, microglia, corpus striatum and spinal cord [79].…”

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

“…Attempts have been made over the years to develop selective A 1 AR agonists that may be useful as antiepileptic agents. Initially the approach for discovering AR agonists as antiepileptics has been restricted to modification of the physiological agonist adenosine [ 26 ], and justly, these adenosine derivatives represent the great majority of molecules developed and reported to date [ 27 ]. The development of these agonists has been limited by the essential requirement of the retention of the ribose moiety of adenosine for agonist activity [ 26 , 28 , 29 ].…”