Structure activity relationships for derivatives of adenosine‐5′‐triphosphate as agonists at P 2 purinoceptors: Heterogeneity within P 2x and P 2y subtypes

The structure‐activity relationships for a variety of adenine nucleotide analogues at P 2X and P 2Y ‐purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N 6 ‐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 P 2Y ‐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 P 2X ‐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 P 2X ‐ or the P 2Y ‐purinoceptors. Certain analogues displayed selectivity or specificity within the P 2X ‐ or P 2Y ‐purinoceptor superfamilies, giving hints about possible subclasses. For example, 8‐(6‐aminohexylamino)ATP and 2′,3′‐isopropylidene‐AMP were selective for endothelial P 2Y ‐purinoceptors over P 2Y ‐purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P 2X ‐purinoceptors. The potent agonist N 6 ‐methyl ATP and the somewhat less potent agonist 2′‐deoxy‐ATP were selective for P 2Y ‐purinoceptors in the guinea pig taenia coli, but were inactive at P 2X ‐purinoceptors and the vascular P 2Y ‐purinoceptors. 3′‐Benzylamino‐3′‐deoxyATP was very potent at the P 2X ‐purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P 2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P 2X ‐ and P 2Y ‐purinoceptor classes. © 1994 Wiley‐Liss, Inc.