P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (seven types; P2X1-7) contain intrinsic pores that open by binding with ATP, and P2Y receptors (eight types; P2Y1,2,4,6,11-14) are activated by nucleotides and couple to intracellular second-messenger systems through heterotrimeric G-proteins. The P2Y1 and P2Y2 receptors are expressed in most human tissues including the heart, placenta, vascular endothelia, prostate, ovary, platelets and brain. They are attractive pharmaceutical targets due to their involvement in the modulation of various functions in many tissues and organs under both normal and pathophysiological conditions. P2Y1 agonists may have potential as antihypertensive or antidiabetic agent. P2Y2 receptor is a target in therapeutics of pulmonary diseases such as cystic fibrosis, and ophtalmic diseases. P2Y1 receptor is activated by ADP, while P2Y2 is activated equipotently by both ATP and UTP (1). Recently, we have synthesized the 2’- and 3’-C-methyl derivatives of ADP and evaluated their capacity to promote hP2Y1 and hP2Y2 receptor-mediated activation of PLC at recombinant human receptors expressed in atrocytoma cells. From the functional assay 2’-C-methyl-ADP resulted a full agonist at P2Y1 receptor, while 3’-Cmethyl- ADP acted as partial agonist at P2Y2 receptor. Having a nucleotide scaffold, these compounds suffer from limitations due their chemical and metabolic instability. One of the approaches to overcome the inherent instability of nucleotide-based drug candidates include the use of isoster-based non-hydrolyzable nucleotides. Based on these considerations, the (methylene)bisphosphonate derivatives of 2’-Cmethyl-, and 3’-C-methyl-adenosine were synthesized and evaluated for their capacity to promote hP2Y1 and hP2Y2 receptor-mediated activation of PLC at recombinant human receptors expressed in astrocytoma cells. The results of the functional assay will be discussed.

Synthesis and biological evaluation of (methylene)bisphosphonate derivatives of 2’-C-methyl-, and 3’-C-methyl-adenosine

CAPPELLACCI, Loredana;PETRELLI, Riccardo;VITA, PATRIZIA;TORQUATI, ILARIA;
2012-01-01

Abstract

P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (seven types; P2X1-7) contain intrinsic pores that open by binding with ATP, and P2Y receptors (eight types; P2Y1,2,4,6,11-14) are activated by nucleotides and couple to intracellular second-messenger systems through heterotrimeric G-proteins. The P2Y1 and P2Y2 receptors are expressed in most human tissues including the heart, placenta, vascular endothelia, prostate, ovary, platelets and brain. They are attractive pharmaceutical targets due to their involvement in the modulation of various functions in many tissues and organs under both normal and pathophysiological conditions. P2Y1 agonists may have potential as antihypertensive or antidiabetic agent. P2Y2 receptor is a target in therapeutics of pulmonary diseases such as cystic fibrosis, and ophtalmic diseases. P2Y1 receptor is activated by ADP, while P2Y2 is activated equipotently by both ATP and UTP (1). Recently, we have synthesized the 2’- and 3’-C-methyl derivatives of ADP and evaluated their capacity to promote hP2Y1 and hP2Y2 receptor-mediated activation of PLC at recombinant human receptors expressed in atrocytoma cells. From the functional assay 2’-C-methyl-ADP resulted a full agonist at P2Y1 receptor, while 3’-Cmethyl- ADP acted as partial agonist at P2Y2 receptor. Having a nucleotide scaffold, these compounds suffer from limitations due their chemical and metabolic instability. One of the approaches to overcome the inherent instability of nucleotide-based drug candidates include the use of isoster-based non-hydrolyzable nucleotides. Based on these considerations, the (methylene)bisphosphonate derivatives of 2’-Cmethyl-, and 3’-C-methyl-adenosine were synthesized and evaluated for their capacity to promote hP2Y1 and hP2Y2 receptor-mediated activation of PLC at recombinant human receptors expressed in astrocytoma cells. The results of the functional assay will be discussed.
2012
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/357384
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