Opposite diastereoselective activation of P2Y 1 and P2Y 11 nucleotide receptors by adenosine 5′-O-(α- boranotriphosphate) analogues

Abstract

Background and purpose: We explored the stereoselective activation of the P2Y 11 receptor, stably expressed and tagged with GFP, in 1321N1 cells, in comparison to its closest homologue, the P2Y 1 receptor. Experimental approach: The potency of several chiral ATP analogues was determined by measuring increases in intracellular calcium concentration ([Ca 2+](i)). In a series of ATP-α-B and ATP-α-S analogues, a non-bridging oxygen atom of P(α) was substituted by BH 3 or sulphur, respectively, introducing a chiral center at P(α). The pairs of diastereoisomers (A and B isomers) were each applied as purified compounds. Key results: The (B) isomers (ATP-α-B Sp isomers and ATP-α-S Rp isomers) of all derivatives tested were more potent at the P2Y 11 receptor than the corresponding (A) isomers (ATP-α-B Rp isomers and ATP-α-S Sp isomers) and the parent compounds. This characteristic of the P2Y 11 receptor is opposite to the behaviour of the same diastereoisomers at the P2Y 1 receptor, at which the (A) isomers are more active. Conclusions and implications: The distinctly opposite diastereoselective activity of ATP derivatives at the P2Y 11 and the P2Y 1 receptor will allow the deciphering of structural differences of the ligand recognition sites between these receptor subtypes and may aid in the development of subtype-selective agonists. Moreover, ATP-α-B diastereoisomers are not active at the P2Y 2 receptor. Thus, they are compounds suitable for distinguishing the functional contribution of the two ATP-activated P2Y receptors, the P2Y 2 and P2Y 11 receptor, in physiological or pathophysiological responses of cells. © 2006 Nature Publishing Group. All rights reserved.