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Partial Agonists for A3 Adenosine Receptors

[ Vol. 4 , Issue. 8 ]


Zhan-Guo Gao and Kenneth A. Jacobson   Pages 855 - 862 ( 8 )


Selective agonists for A3 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 A3AR activation have recently been identified, including the N6-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 A3 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 N6-methyl and N6-benzyl groups may contribute to the A3 affinity and selectivity; however, an N6-benzyl group but not an N6-methyl group diminishes A3AR efficacy. N6-benzyl substituted adenosine derivatives have similar potency for human and rat A3ARs while N6-methyl substitution was preferable for the human A3AR. The combination of 2-chloro and N6-benzyl substitutions appeared to reduce efficacy further than either modification alone. The A2AAR agonist DPMA was shown to be an antagonist for the human A3AR. Thus, the efficacy of adenosine derivatives at the A3AR appears to be more sensitive to small structural changes than at other subtypes. Potent and selective partial agonists for the A3AR could be identified by screening known adenosine derivatives and by modifying adenosine and the adenosine derivatives.


a3 adenosine receptors, methanocarba substitution, 2-chloroadenosine, adenosine derivatives


Molecular Recognition Section, Bldg. 8A, Rm. B1A-23, NIH, NIDDK, LBC, Bethesda, MD 20892-0810,USA.

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