Fluorosulfonyl-substituted xanthines as selective irreversible antagonistsfor the Al-adenosine receptor

FSCPX (1) has been reported to be a potent, selective, and irreversible ant agonist for the A(1)-adenosine receptor (AR). To obtain an irreversible A(1 )AR antagonist with potentially better stability and to further elucidate t he effects of linker structure on the pharmacological characteristics, seve ral new analogues were targeted in which the labile ester linkage of 1 was replaced by more stable functionalities. In particular, alkyl and:amide lin kers between the xanthine pharmacophore and the reactive 4-fluorosulfonylph enyl group were explored. The data showed that the chemical composition of the linker affects the affinity and apparent irreversible binding to the A( 1)AR. Overall, compound 23b appeared to have the most advantageous characte ristics as a potential irreversible ligand for the A(1)AR. These include re latively high affinity for the A(1)AR. as compared to the A(2A)AR, concentr ation-dependent and selective apparent irreversible binding to the A(1)AR, and ease;of removal of unbound ligand from biological membranes. These :pro perties indicate that 23b has the potential to be a useful tool for further study of the structure and function of the A(1)AR.