Synthesis and structure–activity relationships of carboxylic acid derivatives of pyridoxal as P2X receptor antagonists

Jung, Kwan‐Young; Cho, Joong‐Heui; Lee, Jung Sun; Kim, Hyo Jun; Kim, Yong-Chul

doi:10.1016/j.bmc.2013.01.073

Cited by 16 publications

(6 citation statements)

References 43 publications

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“…Next, we introduced an m -phenoxyphenyl group at the 2-position of the pyridine moiety (Table ), which was previously reported as an alternative pharmacophore to a p -methoxyphenethyl group with improved selectivity profiles . However, a 3,4-dicarboxy-2- m -phenoxyphenyl derivative, compound 27 (IC 50 = 301 nM), enhanced neither the hP2X3R antagonistic effect nor the selectivity vs mP2X1R compared with the corresponding 2- p -methoxyphenethyl analogue, 13d .…”

Section: Resultsmentioning

confidence: 99%

“…Afferent Pharmaceutical’s clinical drug candidate, AF-219, , which is a potent and orally bioavailable selective P2X3-P2X2/3 receptor antagonist, has been studied in several proof-of-concept Phase 2 clinical trials, including interstitial cystitis/bladder pain syndrome and chronic cough, which showed a meaningful pharmacological effect. Our group reported potent selective and noncompetitive peptide antagonists, Spinorphin ( 5 , IC 50 = 8.3 pM) and 5-hydroxy pyridine derivatives ( 7a – c ), , which were developed from the modification of the strong anionic phosphate sulfonic acid groups and an unstable azo (−NN−) linkage of a nonselective P2X antagonist, PPADS ( 6a ), to a weak anionic carboxylic acid and a stable carbon–carbon bond, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors

Jung

Kim²,

Cho

et al. 2017

ACS Chem. Neurosci.

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Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Aδ-fiber primary afferent neurons, which are related to the pain-sensing system. In this study, 5-hydroxy pyridine derivatives were designed, synthesized, and evaluated for their in vitro biological activities by two-electrode voltage clamp assay at hP2X3 receptors. Among the novel hP2X3 receptor antagonists, intrathecal treatment of compound 29 showed parallel efficacy with pregabalin (calcium channel modulator) and higher efficacy than AF353 (P2X3 receptor antagonist) in the evaluation of its antiallodynic effects in spinal nerve ligation rats. However, because compound 29 was inactive by intraperitoneal administration in neuropathic pain animal models due to low cell permeability, the corresponding methyl ester analogue, 28, which could be converted to compound 29 in vivo, was investigated as a prodrug concept. Intravenous injection of compound 28 resulted in potent antiallodynic effects, with ED values of 2.62 and 2.93 mg/kg in spinal nerve ligation and chemotherapy-induced peripheral neuropathy rats, respectively, indicating that new drug development targeting the P2X3 receptor could be promising for neuropathic pain, a disease with high unmet medical needs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors

Jung

Kim²,

Cho

et al. 2017

ACS Chem. Neurosci.

Self Cite

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“…Nevertheless, these compounds have been useful for in vitro and in vivo studies to investigate the function of the P2X1 receptor [ 17 , 48 ]. PPADS is a selective P2 receptor antagonist whose drug properties were improved to create a series of antagonists, including MRS2159 and compound 1, which are low molecular weight compounds that are selective for the P2X1 receptor [ 76 , 77 ]. Several research groups have identified novel P2X1 receptor antagonists.…”

Section: P2x1 Drug Discoverymentioning

confidence: 99%

The P2X1 receptor as a therapeutic target

Bennetts

Mobbs

Ventura

et al. 2022

Purinergic Signalling

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Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function. Specifically, the P2X1 receptor has been implicated in controlling smooth muscle contractions of the vas deferens and therefore has emerged as an exciting drug target for male contraception. In addition, the P2X1 receptor contributes to smooth muscle contractions of the bladder and is a target to treat bladder dysfunction. Finally, platelets and neutrophils have populations of P2X1 receptors that could be targeted for thrombosis and inflammatory conditions. Drugs that specifically target the P2X1 receptor have been challenging to develop, and only recently have small molecule antagonists of the P2X1 receptor been available. However, these ligands need further biological validation for appropriate selectivity and drug-like properties before they will be suitable for use in preclinical models of disease. Although the atomic structure of the P2X1 receptor has yet to be determined, the recent discovery of several other P2X receptor structures and improvements in the field of structural biology suggests that this is now a distinct possibility. Such efforts may significantly improve drug discovery efforts at the P2X1 receptor.

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“…[17][18][19] In recent decades, research groups have employed structure-activity relationship studies with known P2X1 receptor ligands or screening methods to discover improved P2X1 receptor ligands. The most promising candidates include PSB-2001, ATA, MRS2159, and the compound series introduced by Jung et al [20][21][22][23] Yet, none are as potent or P2X receptor selective as an older generation P2X1 receptor antagonist, NF449. 24,25 It is important to note that NF449 also exhibits several off-target effects and is a large polar molecule making it difficult to improve.…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the human P2X1 receptor and ligand interactions

Bennetts,

Venugopal,

Glukhova

et al. 2024

Preprint

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The P2X1 receptor is a trimeric ligand-gated ion channel that plays a pivotal role in urogenital and immune functions. Consequently, it offers numerous potential indications for novel drug treatments. Unfortunately, the progress of drug discovery targeting the P2X1 receptor has been impeded by the absence of structural information. To gain deeper insights into the binding site of the P2X1 receptor, we employed cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in both an ATP-bound desensitised state and an NF449-bound closed state. NF449 is a potent P2X1 receptor antagonist and engages with the receptor in a distinctive manner. To gain insights into the molecular machinery governing receptor inhibition and activation and better understand P2X1 receptor ligand subtype selectivity, critical P2X1 receptor residues involved in ligand binding were mutated. Radioligand binding assays with [3H]-α,β-methylene ATP and intracellular calcium influx were employed to assess the effect of these mutations on ligand binding and receptor activation, thereby validating key ligand-receptor interactions. This research expands our understanding of the P2X1 receptor structure at a molecular level and opens new avenues for in silico drug design targeting the P2X1 receptor.

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Synthesis and structure–activity relationships of carboxylic acid derivatives of pyridoxal as P2X receptor antagonists

Cited by 16 publications

References 43 publications

Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors

Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors

The P2X1 receptor as a therapeutic target

Structural insights into the human P2X1 receptor and ligand interactions

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