Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region

SRP-001 is proposed as a non-opioid, non-hepatotoxic analgesic alternative to acetaminophen (ApAP), aiming to avoid ApAP's toxic metabolite formation. In CD-1 mice, SRP-001 showed no mortality at doses where equimolar ApAP caused high mortality within 72 hours. The paper reports that SRP-001 preserves hepatic tight junction integrity and does not generate N-acetyl-p-benzoquinone-imine (NAPQI), unlike ApAP. Antinociceptive effects are reported to be comparable to ApAP across pain models, with both linked to AM404 formation in the midbrain periaqueductal gray (PAG). Single-cell transcriptomics of the PAG is used to connect mechanism to gene and pathway changes, including shared modulation of pain-related networks involving endocannabinoid signaling, FAAH, 2-AG, cannabinoid receptors (CNR1, CNR2), TRPV4, and calcium channel-related signals. A Phase 1 trial (NCT05484414) is mentioned as evidence for SRP-001 safety, tolerability, pharmacokinetics, and a half-life in the ~4.9 to 9.8 hour range.