Abstract
We previously reported a structure–activity study which identified Acid blue 129 (1‐amino‐4‐(2,4,6‐trimethylphenylamino)‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐sulfonic acid) as a highly selective antagonist at the P2Y‐receptor of the guinea pig taenia coli. In contrast to the less selective P2Y‐receptor antagonist Acid blue 25 (1‐amino‐4‐phenylamino‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐sulfonic acid) with its unsubstituted phenyl ring, Acid blue 129 does not show any effect at the P2X‐receptor of the rat vas deferens. It was hypothesized that the nonplanar orientation of the substituted phenyl ring vs. the anthraquinone core, caused by the buttressing methyl groups in 2′,6′‐position, prevents binding of Acid blue 129 to the P2X‐receptor. To prove this assumption we synthesized new compounds structurally related to Acid blue 129. The effects of all compounds were studied on contractions of the rat vas deferens elicited by α,β‐methylene ATP (α,β‐MeATP; mediated by P2X‐receptors) and relaxations of the carbachol‐precontracted guinea pig taenia coli elicited by adenosine 5′‐O‐(2‐thiodiphosphate) (ADPβS; mediated by P2Y‐receptors). All compounds were more or less P2Y‐ vs. P2X‐selective. In contrast to our assumption, it is the 4′‐methyl group of Acid blue 129 and of its new analog MG 32 (1‐amino‐4‐(4‐methylphenylamino)‐9,10‐dioxo‐9,10‐dihydroanthracene‐2‐sulfonic acid) which completely prevents binding to the P2X‐receptor up to 100 μM antagonist concentration, whereas the P2X‐receptor is blocked by related compounds lacking the 4′‐methyl group. Acid blue 129 and MG 32 were the most interesting compounds. Both turned out to be potent P2Y‐receptor antagonists with IC~50~‐values of approximately 3 μM. They are highly selective vs. both P2X‐receptor and non‐P2‐receptor effects. Drug Dev. Res. 59:64–71, 2003. © 2003 Wiley‐Liss, Inc.