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The angiotensin II type 2 receptor antagonists, PD123,319 ((S-( +)-1-[(4-(dimethylamino)-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), EMA300 (5-(2,2-diphenylacetyl)-4-[(4-methoxy-3-methylphenyl)methyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid) and EMA401 ((3S)-5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), evoke pain relief in a varicella zoster virus-induced rat model of neuropathic pain.

作者信息

Das V, Lam A L, Smith M T

机构信息

Centre for Integrated Preclinical Drug Development (CIPDD), School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia Campus, Brisbane, QLD, 4072, Australia.

出版信息

Inflammopharmacology. 2025 Mar;33(3):1337-1348. doi: 10.1007/s10787-025-01650-z. Epub 2025 Feb 20.


DOI:10.1007/s10787-025-01650-z
PMID:39976667
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11913958/
Abstract

Post-herpetic neuralgia (PHN) is a type of neuropathic (nerve) pain that persists for more than 3 months after crusting of the last shingles lesion. It is difficult to relieve with analgesic/adjuvant medications, and so novel analgesics are needed. Our aim was to use a rat model of varicella zoster virus (VZV)-induced neuropathic pain to assess the pain relief efficacy of several small molecule angiotensin II type 2 (AT) receptor antagonists (PD123,319, EMA300, and EMA401) relative to clinically used analgesic/adjuvant agents from four different pharmacological classes. Male Wistar rats received a unilateral intraplantar injection of VZV-infected MRC-5 cells (2 × 10 infected cells) and paw withdrawal thresholds (PWTs) in the ipsilateral hindpaws were assessed using von Frey filaments. Animals with PWTs ≤ 8 g received single doses of PD123,319 (0.03-3 mg/kg), EMA300 (0.3-5 mg/kg), EMA401 (0.03-1 mg/kg), gabapentin (10-60 mg/kg), amitriptyline (5-30 mg/kg), morphine (0.1-3 mg/kg), meloxicam (5-20 mg/kg) or vehicle and PWT versus time curves were generated. Single doses of PD123,319, EMA300, EMA401, gabapentin and morphine-evoked dose-dependent anti-allodynia in the hindpaws of VZV-rats. The mean (95% confidence intervals) EDs were 0.57 (0.04-1.7), 2.5 (1.0-3.7) and 0.41 (0.12-0.87) mg/kg for PD123,319, EMA300, and EMA401, respectively. The EDs for gabapentin and morphine were 39.9 (25.1-64.8) and 0.04 (0.16-2.09) mg/kg, respectively. In conclusion, the anti-allodynic efficacy of EMA401 in a VZV-rat model of neuropathic pain is aligned with its analgesic efficacy in a Phase 2a clinical trial in patients with PHN. This model has utility for anti-allodynic efficacy assessment of novel AT receptor antagonists from drug discovery.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/29c7bc51fcab/10787_2025_1650_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/3058a0fa7d7e/10787_2025_1650_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/49ab92342061/10787_2025_1650_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/80833f3cb9ac/10787_2025_1650_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/b35a80e4a0ab/10787_2025_1650_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/29c7bc51fcab/10787_2025_1650_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/3058a0fa7d7e/10787_2025_1650_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/49ab92342061/10787_2025_1650_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/80833f3cb9ac/10787_2025_1650_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/b35a80e4a0ab/10787_2025_1650_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b60/11913958/29c7bc51fcab/10787_2025_1650_Fig5_HTML.jpg

相似文献

[1]
The angiotensin II type 2 receptor antagonists, PD123,319 ((S-( +)-1-[(4-(dimethylamino)-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), EMA300 (5-(2,2-diphenylacetyl)-4-[(4-methoxy-3-methylphenyl)methyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid) and EMA401 ((3S)-5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), evoke pain relief in a varicella zoster virus-induced rat model of neuropathic pain.

Inflammopharmacology. 2025-3

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本文引用的文献

[1]
Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation.

Curr Opin Pharmacol. 2023-12

[2]
Efficacy of gabapentinoids for acute herpes zoster in preventing postherpetic neuralgia: a systematic review of randomized controlled trials.

Dermatol Online J. 2022-10-15

[3]
A Meta-analysis of Randomized Controlled Trials Comparing the Efficacy and Safety of Pregabalin and Gabapentin in the Treatment of Postherpetic Neuralgia.

Pain Ther. 2023-2

[4]
Angiotensin type 2 receptor antagonism as a new target to manage gout.

Inflammopharmacology. 2022-12

[5]
Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial.

Pain. 2022-11-1

[6]
Discovery and Optimization of Highly Potent and Selective ATR Antagonists to Relieve Peripheral Neuropathic Pain.

ACS Omega. 2021-5-28

[7]
Use of Cyclic Ion Mobility Spectrometry (cIM)-Mass Spectrometry to Study the Intramolecular Transacylation of Diclofenac Acyl Glucuronide.

Anal Chem. 2021-5-25

[8]
MRC5 cells engineered to express ACE2 serve as a model system for the discovery of antivirals targeting SARS-CoV-2.

Sci Rep. 2021-3-8

[9]
Efficacy and safety of EMA401 in peripheral neuropathic pain: results of 2 randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy.

Pain. 2021-10-1

[10]
An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy.

Sci Rep. 2018-11-6

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