Structure activity relationships for derivatives of adenosine‐5′‐triphosphate as agonists at P2 purinoceptors: Heterogeneity within P2x and P2y subtypes

Abstract

The structure‐activity relationships for a variety of adenine nucleotide analogues at P2X and P2Y‐purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N6‐substituents, and a uridine base instead of adenine), the ribose moiety (2′ and 3′‐positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P2Y‐purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P2X‐purinoceptors was assayed in the rabbit saphenous artery and the guinea‐pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P2X‐ or the P2Y‐purinoceptors. Certain analogues displayed selectivity or specificity within the P2X‐ or P2Y‐purinoceptor superfamilies, giving hints about possible subclasses. For example, 8‐(6‐aminohexylamino)ATP and 2′,3′‐isopropylidene‐AMP were selective for endothelial P2Y‐purinoceptors over P2Y‐purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P2X‐purinoceptors. The potent agonist N6‐methyl ATP and the somewhat less potent agonist 2′‐deoxy‐ATP were selective for P2Y‐purinoceptors in the guinea pig taenia coli, but were inactive at P2X‐purinoceptors and the vascular P2Y‐purinoceptors. 3′‐Benzylamino‐3′‐deoxyATP was very potent at the P2X‐purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P2X‐ and P2Y‐purinoceptor classes. © 1994 Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc.