8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors

Article abstract of DOI:10.1021/jm00083a018

With the aim of characterizing the hydrophobic interactions between xanthines and the A₁ receptor site, 1,3-dipropyl-8-substituted xanthines were synthesized. Introduction of a quaternary carbon and the conformationally restricted cyclopentyl moiety into the 8-position of xanthines enhanced the adenosine A₁ antagonism. 1,3-Dipropyl-8-(3- noradamantyl)xanthine (42) was identified to be a selective and the most potent A₁ receptor antagonist reported to date. Under our structure-activity relationship, the 8-substituent of xanthine antagonists and the N⁶- substituent of adenosine agonists appears to bind to the same region of the A₁ receptor.