当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design and synthesis of potent and selective P2X₃ receptor antagonists derived from PPADS as potential pain modulators.

Design and synthesis of potent and selective P2X₃ receptor antagonists derived from PPADS as potential pain modulators.

Abstract：

:Pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X₃ receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS including phosphate and sulfonate groups were changed to carboxylic acids or deleted. The unstable azo (-NN-) linkage of 7a was transformed to more stable carbon-carbon, ether or amide linkages through the synthesis of the 5-hydroxyl-pyridine moieties with substituents at 2 position via a Diels-Alder reaction. This resulted in the retention of antagonistic activity (IC50 = 400 ∼ 700 nM) at the hP2X₃ receptor in the two-electrode voltage clamp (TEVC) assay system on the Xenopus oocytes. Introduction of bulky aromatic groups at the carbon linker, as in compounds 13 h-n, dramatically improved the selectivity profiles of hP2X₃ when compared with mP2X₁ and hP2X₇ receptors. Among the substituents tested at the 2-position, the m-phenoxybenzyl group showed optimum selectivity and potency at the hP2X₃ receptor. In searching for effective substituents at the 4- and 3-positions, we found that compound 36j, with 4-carboxaldehyde, 3-propenoic acid and 2-(m-phenoxy)benzyl groups, was the most potent and selective hP2X₃ receptor antagonist with an IC50 of 60 nM at hP2X₃ and marginal antagonistic activities of 10 μM at mP2X₁ and hP2X₇. Furthermore, using an ex-vivo assay system, we found that compound 36j potently inhibited pain signaling in the rat dorsal horn with 20 μM 36j displaying 65% inhibition while 20 μM pregabalin, a clinically available drug, showed only 31% inhibition.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Cho JH,Jung KY,Jung Y,Kim MH,Ko H,Park CS,Kim YC

doi

10.1016/j.ejmech.2013.10.026

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

811-30

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(13)00667-3

journal_volume

70

pub_type

杂志文章

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