Partial agonists for A(3) adenosine receptors.

Selective agonists for A(3) adenosine receptors (ARs) could potentially be therapeutic agents for a variety of disorders, including brain and heart ischemic conditions, while partial agonists may have advantages over full agonists as a result of an increased selectivity of action. A number of structural determinants for A(3)AR activation have recently been identified, including the N(6)-benzyl group, methanocarba substitution of ribose, 2-chloro and 2-fluoro substituents, various 2'- and 3'-substitutions and 4'-thio substitution of oxygen. The 2-chloro substitution of CPA and R-PIA led to A(3) antagonism (CCPA) and partial agonism (Cl-R-PIA). 2-Chloroadenosine was a full agonist, while 2-fluoroadenosine was a partial agonist. Both 2'- and 3'- substitutions have a pronounced effect on its efficacy, although the effect of 2'-substitution was more dramatic. The 4-thio substitution of oxygen may also diminish efficacy, depending on other substitutions. Both N(6)-methyl and N(6)-benzyl groups may contribute to the A(3) affinity and selectivity; however, an N(6)-benzyl group but not an N(6)-methyl group diminishes A(3)AR efficacy. N(6)-benzyl substituted adenosine derivatives have similar potency for human and rat A(3)ARs while N(6)-methyl substitution was preferable for the human A(3)AR. The combination of 2-chloro and N(6)-benzyl substitutions appeared to reduce efficacy further than either modification alone. The A(2A)AR agonist DPMA was shown to be an antagonist for the human A(3)AR. Thus, the efficacy of adenosine derivatives at the A(3)AR appears to be more sensitive to small structural changes than at other subtypes. Potent and selective partial agonists for the A(3)AR could be identified by screening known adenosine derivatives and by modifying adenosine and the adenosine derivatives.