# 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

## TL;DR

This study shows that new angiotensin II type 2 receptor antagonists can relieve neuropathic pain in a rat model, similar to clinical results in humans.

## Contribution

The study demonstrates that AT2 receptor antagonists like EMA401 have anti-allodynic effects in a VZV-induced neuropathic pain model.

## Key findings

- EMA401 showed analgesic efficacy in a rat model of VZV-induced neuropathic pain.
- EMA401's ED50 in rats aligns with its efficacy observed in a Phase 2a clinical trial for PHN.
- PD123,319 and EMA300 also showed dose-dependent anti-allodynic effects in the model.

## 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.

The online version contains supplementary material available at 10.1007/s10787-025-01650-z.