title: Synthesis and structure-activity relationships of carboxylic acid derivatives of pyridoxal as P2X receptor antagonists.
abstract: Carboxylic acid derivatives of pyridoxal were developed as potent P2X(1) and P2X(3) receptor antagonists with modifications of a lead compound, pyridoxal-5'-phosphate-6-azophenyl-2',5'-disulfonate (5b, iso-PPADS). The designing strategies included the modifications of aldehyde, phosphate or sulfonate groups of 5b, which may be interacted with lysine residues of the receptor binding pocket, to weak anionic carboxylic acid groups. The corresponding carboxylic acid analogs of pyridoxal-5'-phosphate (1), 13 and 14, showed parallel antagonistic potencies. Also, most of 6-azophenyl derivatives (24-28) of compound 13 or 14 showed potent antagonistic activities similar to that of 5b at human P2X(3) receptors with 100 nM range of IC(50) values in two-electrode voltage clamp (TEVC) assay system on the Xenopus oocyte. The results indicated that aldehyde and phosphoric or sulfonic acids in 5b could be changed to a carboxylic acid without affecting antagonistic potency at mouse P2X(1) and human P2X(3) receptors.
authors.affiliation: School of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Kwan-Young
authors.initials: KY
authors.lastname: Jung
authors.forename: Joong-Heui
authors.initials: JH
authors.lastname: Cho
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Lee
authors.forename: Hyo Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011730:Pyridoxal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D058920:Purinergic P2X Receptor Antagonists; D058477:Receptors, Purinergic P2X3; D011730:Pyridoxal