ArticleResearch square2023
Transcriptomic signature, bioactivity and safety of a non-hepatoxic analgesic generating AM404 in the mid-brain PAG region.
Article in Research square, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05484414 (A 2 Part Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Pharmacokinetics of SAD/MAD Oral Doses of SRP-3D), which is not on this map. Not yet cited in PubMed.
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A 2 Part Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Pharmacokinetics of SAD/MAD Oral Doses of SRP-3D (DA), and to Characterize the Effect of Food on the Pharmacokinetics in Healthy Male and Female Subjects
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Abstract
The safe and effective management of pain is a critical healthcare and societal need. The potential for misuse and addiction associated with opioids, nephrotoxicity, and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use, as well as acute liver injury from paracetamol (ApAP) overdose, are unresolved challenges. To address them, we developed a non-opioid and non-hepatotoxic small molecule, SRP-001. Compared to ApAP, SRP-001 is not hepatotoxic as it does not produce N-acetyl-p-benzoquinone-imine (NAPQI) and maintains hepatic tight junction integrity at high doses. SRP-001 has comparable analgesia in pain models, including the complete Freund's adjuvant (CFA) inflammatory von Frey. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception area, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways, including the endocannabinoid, mechanical nociception, and fatty acid amide hydrolase (FAAH) pathways. Both regulate the expression of key genes encoding FAAH, 2-AG, CNR1, CNR2, TRPV4, and voltage-gated Ca2+ channel. Interim Phase 1 trial results demonstrate SRP-001's safety, tolerability, and favorable pharmacokinetics (NCT05484414). Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.
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