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 nucleoti de analogues at P-2X- and P-2Y-purinoceptors were investigated. Compou nds formed by structural modifications of the ATP molecule including s ubstitutions of the purine ring (C2, C8, N1, and N-6-substituents, and a uridine base instead of adenine), the ribose moiety (2' and 3'-posi tions), 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, endo thelial cells of the rabbit aorta, smooth muscle of the rabbit mesente ric artery, and turkey erythrocyte membranes. Activity at P-2X-purinoc eptors was assayed in the rabbit saphenous artery and the guinea-pig v as deferens and urinary bladder. Some of the analogues displayed selec tivity, or even specificity, for either the P-2X- or the P-2Y-purinoce ptors. Certain analogues displayed selectivity or specificity within t he P-2X- or P-2Y-purinoceptor superfamilies, giving hints about possib le subclasses. For example, 8-(6-aminohexylamino)ATP and 2',3'-isoprop ylidene-AMP were selective for endothelial P-2Y-purinoceptors over P-2 Y-purinoceptors in the guinea pig taenia coli, rabbit aorta, and turke y erythrocytes. These compounds were both inactive at P-2X-purinocepto rs. The potent agonist N-6-methyl ATP and the somewhat less potent ago nist 2'-deoxy-ATP were selective for P-2Y-purinoceptors in the guinea pig taenia coli, but were inactive at P-2X-purinoceptors and the vascu lar 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-purin oceptor classes. (C) 1994 Wiley-Liss, Inc.