article · ACS Omega
Investigation of Acacia sieberiana, a plant used in African traditional medicine for pain, identified the alkaloid amides piperine and moupinamide from its stem bark through metabolomics-guided fractionation. Moupinamide and its isomer were also chemically synthesised. In animal testing, the bark extract significantly reduced acute pain-related behaviour in a capsaicin-induced mouse model, though it did not alter secondary mechanical sensitivity. Testing on human stem cell-derived sensory neurons demonstrated that moupinamide potently suppressed neuronal electrical firing. Further pharmacological analysis revealed that moupinamide operates through voltage-gated sodium channels, suppressing Nav1.7-related hyperexcitability without significantly interacting with TRPV1 or common G-protein-coupled receptors. These findings highlight these plant-derived alkaloid amides as prospective starting points for developing non-opioid pain treatments.
Many existing pain medications carry risks of dependence or severe side effects, driving interest in non-opioid alternatives. Validating traditional remedies through modern cellular assays and animal models establishes a scientific basis for indigenous knowledge. Identifying plant-derived molecules that suppress pain signalling by modulating specific sodium channels provides valuable leads for future non-addictive pain therapies.
The identified alkaloid amides could inform early-stage drug discovery programmes seeking non-opioid pain treatments, particularly targeting voltage-gated sodium channels such as Nav1.7. Intended users would be pharmaceutical and biotechnology researchers focusing on analgesics. Given that evidence is currently limited to chemical synthesis, in vitro human sensory neuron assays, and acute mouse models, this research represents an early discovery phase far from clinical application or commercial release.
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Abstract Acacia sieberiana (syn. Vachellia sieberiana), widely used in African traditional medicine for pain, was investigated using an ethnopharmacology-guided workflow integrating LC-MS/MS-based metabolomics and molecular networking to prioritize bioactive secondary metabolites. Fractionation of the ethanolic stem bark extract enabled targeted isolation and identification of piperine (1) and moupinamide (3) by HRMS and NMR. Moupinamide and its positional isomer (tamgermanetin) were synthesized via HATU-mediated coupling to support preliminary structure–activity studies. In a capsaicin-induced mouse model, the extract significantly attenuated acute nociceptive behavior without affecting the secondary mechanical hypersensitivity. Functional screening using human iPSC-derived nociceptors in a multielectrode array (MEA) platform showed that moupinamide potently reduced neuronal firing, with reduced efficacy under high-heat conditions, suggesting a non-TRPV1-mediated mechanism. GPCR profiling of moupinamide revealed minimal receptor engagement, and further pharmacological studies demonstrated retained activity under potassium channel blockade and suppression of Nav1.7-induced hyperexcitability, consistent with voltage-gated sodium channel modulation. These findings highlight A. sieberiana-derived alkaloid amides as promising nonopioid analgesic leads and underscore the utility of metabolomics-guided discovery strategies.
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DOI: 10.1021/acsomega.6c06672
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