血管紧张素II 2型受体拮抗剂PD123,319 (（S-（+)-1-[（4-（二甲氨基）-3-甲基苯基）甲基]-5-（二苯基乙酰）-4,5,6,7-四氢- 1h -咪唑[4,5-甲氧基-3-甲基苯基）甲基]-1,4,6,7-四氢咪唑[4,5-c]吡啶-6-羧酸）和EMA401 (（3S)-5-（苯氧基）-2-（2,2-二苯基乙酰基）-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸），在水痘带状疱疹病毒诱导的神经性疼痛大鼠模型中唤起疼痛缓解

IF 4.6 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2025-03-01 Epub Date: 2025-02-20 DOI:10.1007/s10787-025-01650-z

V Das, A L Lam, M T Smith

{"title":"血管紧张素II 2型受体拮抗剂PD123,319 (（S-（+)-1-[（4-（二甲氨基）-3-甲基苯基）甲基]-5-（二苯基乙酰）-4,5,6,7-四氢- 1h -咪唑[4,5-甲氧基-3-甲基苯基）甲基]-1,4,6,7-四氢咪唑[4,5-c]吡啶-6-羧酸）和EMA401 (（3S)-5-（苯氧基）-2-（2,2-二苯基乙酰基）-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸），在水痘带状疱疹病毒诱导的神经性疼痛大鼠模型中唤起疼痛缓解","authors":"V Das, A L Lam, M T Smith","doi":"10.1007/s10787-025-01650-z","DOIUrl":null,"url":null,"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 (AT2) 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 × 104 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) ED50s 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 ED50s 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 AT2 receptor antagonists from drug discovery.","PeriodicalId":13551,"journal":{"name":"Inflammopharmacology","volume":" ","pages":"1337-1348"},"PeriodicalIF":4.6000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913958/pdf/","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"V Das, A L Lam, M T Smith\",\"doi\":\"10.1007/s10787-025-01650-z\",\"DOIUrl\":null,\"url\":null,\"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 (AT2) 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 × 104 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) ED50s 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 ED50s 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 AT2 receptor antagonists from drug discovery.\",\"PeriodicalId\":13551,\"journal\":{\"name\":\"Inflammopharmacology\",\"volume\":\" \",\"pages\":\"1337-1348\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913958/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Inflammopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10787-025-01650-z\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10787-025-01650-z","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/20 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

带状疱疹后神经痛（PHN）是一种神经性疼痛，在带状疱疹最后病变结痂后持续3个月以上。镇痛/辅助药物难以缓解，因此需要新型镇痛药。我们的目的是使用水痘带状疱疹病毒（VZV）诱导的神经性疼痛大鼠模型来评估几种小分子血管紧张素II 2型（AT2）受体拮抗剂（PD123,319， EMA300和EMA401）相对于临床使用的四种不同药理学类别的镇痛/佐剂的疼痛缓解效果。雄性Wistar大鼠单侧足底内注射vzv感染的MRC-5细胞（2 × 104个感染细胞），采用von Frey丝法评估其同侧后肢的爪脱阈值（PWTs）。PWTs≤8 g的动物给予单剂量PD123,319 （0.03-3 mg/kg）、EMA300 （0.3-5 mg/kg）、EMA401 （0.03-1 mg/kg）、加巴喷丁（10-60 mg/kg）、阿米替林（5-30 mg/kg）、吗啡（0.1-3 mg/kg）、美洛昔康（5-20 mg/kg）或载药，并生成PWT随时间的变化曲线。单剂量PD123,319、EMA300、EMA401、加巴喷丁和吗啡诱发vzv大鼠后肢剂量依赖性抗异常性疼痛PD123,319、EMA300和EMA401的平均ed50（95%置信区间）分别为0.57（0.04-1.7）、2.5（1.0-3.7）和0.41 (0.12-0.87)mg/kg。加巴喷丁和吗啡的ed50值分别为39.9（25.1-64.8）和0.04 (0.16-2.09)mg/kg。综上所述，EMA401在vzv -大鼠神经性疼痛模型中的抗异动作用与其在PHN患者2a期临床试验中的镇痛作用是一致的。该模型可用于新发现的AT2受体拮抗剂的抗异动疗效评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

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.

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 (AT₂) 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 × 10⁴ 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) ED₅₀s 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 ED₅₀s 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 AT₂ receptor antagonists from drug discovery.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]