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.

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":"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}

引用次数: 0

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.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

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 [...]