A novel class of highly potent and selective A(1) adenosine antagonists: Structure-affinity profile of a series of 1,8-naphthyridine derivatives

A series of 1,8-naphthyridine derivatives (12-36), bearing a phenyl group in position 2 and various substituents in positions 4 and 7, were synthesized in an attempt to obtain potent, selective antagonists for the A(1) adenosine receptor subtype. The compounds were tested to evaluate their affinity for A(1) compared with A(2A) and A(3) adenosine receptor subtypes. In binding studies in bovine brain cortical membranes, most of the compounds showed an affinity for A(1) receptors in the low nanomolar range and two in the subnanomolar range with an interesting degree of A(1) versus A(2A) and A(3) selectivity. Comparison of the 4-substituted derivatives indicated that 4-OH substitution, with a 4-quinoid structure, causes an increase in the A(1) and A(2A) affinity and generally also in A(1) selectivity. The kind of substitution in position 7 can greatly modulate the affinity: the most interesting substituents in this position seemed to be electron-withdrawing groups; in particular the 7-chloronaphthyridine 25d showed a remarkable selectivity (A(2A)/A(1) ratio of 670, A(3)/A(1) ratio of 14 000) associated with a higher A(1) affinity (K-i = 0.15 nM). NMR studies on these compounds 12-36 indicated that the 4-OH-substituted ones prefer the tautomer in which the oxygen in position 4 is in the quinoid form and the nitrogen in position 1 is protonated. Theoretical calculations are in agreement with the NMR data.