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

Cho, Joong‐Heui; Jung, Kwan‐Young; Jung, Young‐Hwan; Kim, Min Hye; Ko, Hyojin; Park, Chul–Seung; Kim, Yong-Chul

doi:10.1016/j.ejmech.2013.10.026

Cited by 21 publications

(15 citation statements)

References 43 publications

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“…P2X3 receptors are selectively expressed at high levels in nociceptive primary sensory neurons in trigeminal, nodose, and dorsal root ganglia [25]. The selective expression of P2X3 receptors in these areas involved in pain transmission suggested that they may be crucial in processing pain signals, and several studies have evaluated the relationships between P2X3 receptors and pain sensation.…”

Section: Neuronal P2x3 Receptors: Key Players In Nociceptionmentioning

confidence: 99%

The Purinergic System and Glial Cells: Emerging Costars in Nociception

Magni

Ceruti

2014

BioMed Research International

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It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel “druggable” glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states.

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Section: Neuronal P2x3 Receptors: Key Players In Nociceptionmentioning

confidence: 99%

The Purinergic System and Glial Cells: Emerging Costars in Nociception

Magni

Ceruti

2014

BioMed Research International

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“…Although we previously reported a potent antagonist, 7c, with an IC 50 value of 60 nM against hP2X3R for its inhibitory pain signaling activity, the in vitro metabolic stability of 7c was determined to be extremely low (percent remaining after 30 min incubation with S9 microsomal fraction), likely due to the 4-aldehyde group. Therefore, we have tried to optimize the combinations of moieties at the 3, 4 and 6-positions of the 5-hydroxy pyridine skeleton, including modifications of the 4-aldehyde group.…”

Section: Resultsmentioning

confidence: 90%

“… a The ion current responses evoked by 2 μM ATP at the recombinant P2X receptors expressed in Xenopus oocytes. b The % inhibition effects of compounds at 1 μM. c 10 μM. d The IC 50 values were measured for mP2X1 and hP2X3 receptors (mean ± SEM, n ≥ 3). e The ethidium bromide accumulation was measured in hP2X7-expressing HEK293 cells, and the % inhibition of the accumulation by 10 μM of the compounds was evaluated (mean ± SEM, n ≥ 3). f We reported the IC 50 values in a previous study g 1 (A-317491, IC 50 value = 97 nM against the hP2X3 receptor) was reported …”

Section: Resultsmentioning

confidence: 97%

“…To explore the SAR of the 6-position of the 3,4-dicarboxypyridine derivatives, we replaced the methyl group of the 6-position with various alkyl and arylalkyl groups. The synthetic procedures of the previous report were employed, starting from various natural and unnatural amino acids. Briefly, p -methoxy-phenyl propionic acid, 8 , was conjugated with esters of the amino acids to yield 10a – k , which were subsequently cyclized to oxazole analogues, 11a – k , by treatment with phosphorus pentoxide.…”

Section: Chemistrymentioning

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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Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy

Zhang

2021

Purinergic Signalling

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

Cited by 21 publications

References 43 publications

The Purinergic System and Glial Cells: Emerging Costars in Nociception

The Purinergic System and Glial Cells: Emerging Costars in Nociception

Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors

Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy

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