Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y13 receptor.

Abstract

We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxal-5'-phosphate-6-azo-phenyl-2,4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Y13 nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing G(alpha)16 protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5'-alkyl phosphonate analogues were synthesized and tested. A 6-benzyl-5'-methyl phosphonate analogue was prepared to examine the effect of stable replacement of the azo linkage. The highest antagonistic potency was observed for 6-(3-nitrophenylazo) derivatives of pyridoxal-5'-phosphate. The 2-chloro-5-nitro analogue (MRS 2211) and 4-chloro-3-nitro analogue (MRS 2603) inhibited ADP (100 nM)-induced inositol trisphosphate (IP3) formation with pIC50 values of 5.97 and 6.18, respectively, being 45- and 74-fold more potent than PPADS. The antagonism of MRS 2211 was competitive with a pA2 value of 6.3. MRS2211 and MRS2603 inhibited phospholipase C (PLC) responses to 30 nM 2-methylthio-ADP in human P2Y1 receptor-mediated 1321N1 astrocytoma cells with IC50 values of >10 and 0.245 microM, respectively. Both analogues were inactive (IC50>10 microM) as antagonists of human P2Y12 receptor-mediated PLC responses in 1321N1 astrocytoma cells. Thus, MRS2211 displayed >20-fold selectivity as antagonist of the P2Y13 receptor in comparison to P2Y1 and P2Y12 receptors, while MRS2603 antagonized both P2Y1 and P2Y13 receptors.

• Authors: Yong-Chul Kim, Jung-Sun Lee, Katrin Sak, Frederic Marteau, Liaman Mamedova, Jean-Marie Boeynaems, Kenneth A Jacobson
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 70 Issue 2 Pg. 266-74 (Jul 15 2005) ISSN: 0006-2952 [Print] England
• PMID: 15913566 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• P2RY13 protein, human
• Purinergic P2 Receptor Antagonists
• Receptors, Purinergic P2
• Pyridoxal Phosphate

Topics

• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Purinergic P2 Receptor Antagonists
• Pyridoxal Phosphate (analogs & derivatives, chemical synthesis, pharmacology)
• Receptors, Purinergic P2 (physiology)
• Structure-Activity Relationship