Selective A3AR agonists are sought as potential agents for treating inflammatory diseases,
chronic pain, cancer and non-alcoholic steatohepatitis (NASH). NIDDK investigators have invented 
new chemical composition as positive allosteric modulators (PAMs) of the A3AR. These chemical 
compounds contain sterically constrained, bridged modifications and cycloalkyl rings of various 
sizes, as well as modifications of the 4-arylamino group. The compounds have added 
three-dimensionality to otherwise flat molecules, which helps distinguish their positive (desired) 
and negative (undesired) pharmacological effects on the action of A3AR agonists. Unlike agonists 
that have side effects, PAM action can be event- and site-specific because adenosine is 
endogenously elevated in response to localized distress
signals within the body.