Paynantheine

Paynantheine

Paynantheine Overview

Paynantheine is one of the most abundant minor alkaloids in Mitragyna speciosa (kratom), typically accounting for 10–15% of total alkaloid content. Chemically, it is an indole alkaloid with a molecular weight of 408.48 g/mol. Unlike the opioid receptor agonists Mitragynine and 7-Hydroxymitragynine, Paynantheine functions primarily as a competitive antagonist at μ- and κ-opioid receptors while demonstrating strong serotonergic activity, especially at 5-HT₁A receptors (Ki ~32 nM). This dual profile suggests it plays a modulatory role in kratom’s pharmacological effects rather than acting as a primary psychoactive driver.

Comparative analysis shows that Paynantheine’s unique receptor interactions may contribute to mood regulation, analgesic modulation, and autonomic balance. Toxicological evidence indicates a favorable safety profile, with low direct opioid toxicity, although no LD₅₀ has been determined in animal models. Preliminary studies suggest hepatic metabolism through CYP450 enzymes, raising the possibility of drug interactions.

Future research should prioritize controlled pharmacological assays, metabolic characterization, and clinical studies to confirm therapeutic applications in anxiety, depression, and neuropathic pain. Collectively, Paynantheine represents an important example of kratom’s polypharmacology and may contribute to the development of safer, more targeted therapeutics.

Introduction

Kratom (Mitragyna speciosa), a tropical tree native to Southeast Asia, has gained global attention for its complex pharmacological profile and traditional use as a stimulant and analgesic (Frontiers in Pharmacology). Its psychoactive effects are attributed to over 40 identified alkaloids, the most studied being Mitragynine and 7-Hydroxymitragynine, both of which act as opioid receptor agonists [1].

Among the secondary alkaloids, Paynantheine stands out as the second-most abundant compound (10–15%), surpassed only by Mitragynine [2]. Despite its abundance, Paynantheine has been comparatively understudied, with limited data on its pharmacological and toxicological properties. Early findings, however, reveal a distinct receptor profile, functioning as an opioid antagonist while exhibiting serotonin receptor modulation [3].

This dual pharmacology highlights Paynantheine as a potentially important contributor to kratom’s overall effects. Unlike Mitragynine and 7-OH Mitragynine, which drive the plant’s opioid-like properties, Paynantheine may act as a pharmacological modulator, reducing risks of opioid overstimulation while supporting mood-regulating pathways.

Objectives of the Paper
  • To provide a comprehensive pharmacological profile of Paynantheine, including chemical identity, abundance, detection, and receptor binding.
  • To analyze its opioid and non-opioid receptor interactions.
  • To compare its pharmacology and safety profile with other major kratom alkaloids.
  • To assess its toxicological properties and discuss implications for human safety.
  • To explore its therapeutic potential and research gaps for future investigation.

Comprehensive Profile of Paynantheine

Identity & Official Identifiers
  • Name: Paynantheine
  • PubChem CID: 3037629 [4]
  • CAS RN: 4697-66-9 [5]
  • UNII: YLG43M4U5V [6]
  • ChEMBL ID: CHEMBL4848517 [7]
  • MeSH Descriptor: M0584431 [8]
  • Class: Indole alkaloid (corynanthe-type, heterotetracyclic indolo[2,3-a]quinolizine)
Chemical Formula & Properties
  • Molecular formula: C₂₃H₂₈N₂O₄
  • Molecular weight: 396.5 g/mol (PubChem release 2025.04.14)
  • IUPAC: methyl (E)-2-[(2S,3R,12bS)-3-ethenyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-2-yl]-3-methoxyprop-2-enoate
  • XLogP3-AA: 3.2 (moderate lipophilicity)
  • Topological polar surface area: 63.8 Ų
Identifier Value Source
PubChem CID 3037629 PubChem [9]
CAS RN 4697-66-9 CAS Common Chemistry [10]
UNII YLG43M4U5V FDA GSRS (UNII) [11]
ChEMBL CHEMBL4848517 ChEMBL compound view [12]
MeSH Concept M0584431 NLM MeSH entry [13]
InChIKey JGZKIGWXPPFMRG-CYSPOEIOSA-N PubChemLite mirror [14]

0.032 0.410 2.600 5-HT1A MOR (μ) KOR (κ) Ki (μM, log scale)
Figure 1. Paynantheine receptor binding affinities

Abundance & Composition
  • Abundance: typically 10–15% of total alkaloids in kratom leaves
  • Extract composition example: mitragynine 48.6%, paynantheine 5.8% (alkaloid extract, in vivo study)
  • Commercial product survey: Paynantheine detected above 0.1% w/w in many kratom products
Receptor Pharmacology
  • Serotonin (5-HT):
    • 5-HT₁A: Kᵢ ≈ 32 nM → high affinity
    • 5-HT₂B: sub-µM binding reported
  • Opioid:
    • μ-Opioid receptor (MOR): Kᵢ ≈ 0.41 µM (antagonist-like)
    • κ-Opioid receptor (KOR): Kᵢ ≈ 2.6 µM
    • δ-Opioid receptor (DOR): no measurable binding <10 µM

Metabolism & Biomarkers
  • Phase I/II metabolism in rat urine: O-demethylation, hydroxylation, carboxylation; conjugated as glucuronides/sulfates
  • Same metabolites detected in human urine: Paynantheine is a forensic biomarker of kratom use
Toxicology / Regulatory Context
  • WHO (2021): kratom alkaloids, including Paynantheine, are not placed under international control, but under surveillance
  • FDA (2025): warns against kratom use; no approvals for kratom alkaloids
  • Toxicology data: No LD₅₀ or isolated human toxicology data available

Discussion

  • Secondary but abundant alkaloid: Paynantheine is a secondary but abundant alkaloid of Mitragyna speciosa.
  • Receptor profile: Unlike Mitragynine or 7-OH Mitragynine, it shows weak or antagonistic opioid receptor activity but strong serotonergic action (5-HT₁A).
  • Pharmacological implications:
    • Functions more as a modulator than a direct psychoactive driver.
    • By antagonizing μ- and κ-opioid receptors, it may buffer kratom’s overall opioid load, reducing overstimulation risk.
    • 5-HT₁A activity supports roles in mood regulation, anxiolysis, and non-opioid antinociception.
  • Metabolic studies: Distinct conjugates detectable in humans, making it important for forensic/toxicological panels.
  • Overall contribution: Paynantheine represents polypharmacology: it contributes to kratom’s effects through non-opioid mechanisms while tempering strong MOR agonists like 7-OH Mitragynine.

Conclusion

Paynantheine, a major secondary alkaloid in Mitragyna speciosa, differs fundamentally from Mitragynine and 7-Hydroxymitragynine. Instead of acting as an opioid agonist, it serves as a competitive antagonist at μ- and κ-opioid receptors while showing high affinity for serotonergic sites, especially 5-HT₁A. This positions it as a modulator in kratom’s pharmacology, contributing to mood regulation and analgesic balance without driving strong opioid effects.

Available evidence suggests a favorable safety profile, with lower toxicity risk than kratom’s primary opioid alkaloids. However, critical knowledge gaps remain, including limited toxicological data and the absence of human clinical trials.

Overall, Paynantheine appears to be a key balancing compound in kratom’s alkaloid mix. Further research, particularly on its metabolic pathways, safety, and therapeutic applications, will be essential to determine its role in future pharmacological and clinical contexts.

References

  1. ACS Journal of Natural Products. (n.d.). Kratom alkaloid pharmacology. American Chemical Society. https://pubs.acs.org/journal/jnprdf
  2. ScienceDirect. (n.d.). Kratom alkaloid content. Elsevier. https://www.sciencedirect.com
  3. National Center for Biotechnology Information (NCBI). (n.d.). Kratom alkaloid pharmacology. PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/
  4. PubChem. (2025). Paynantheine (CID: 3037629). National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/compound/3037629
  5. CAS Common Chemistry. (n.d.). 4697-66-9 Paynantheine. American Chemical Society. https://commonchemistry.cas.org/detail?cas_rn=4697-66-9
  6. FDA Global Substance Registration System (GSRS). (n.d.). YLG43M4U5V Paynantheine. U.S. Food and Drug Administration. https://gsrs.ncats.nih.gov/ginas/app/beta/substances/YLG43M4U5V
  7. ChEMBL. (n.d.). CHEMBL4848517 Paynantheine. European Bioinformatics Institute (EMBL-EBI). https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL4848517
  8. National Library of Medicine. (n.d.). MeSH Descriptor: Paynantheine (M0584431). Medical Subject Headings (MeSH). https://id.nlm.nih.gov/mesh/M0584431.html
  9. PubChemLite. (2025). Paynantheine InChIKey JGZKIGWXPPFMRG-CYSPOEIOSA-N. European Bioinformatics Institute (EMBL-EBI). https://pubchemlite.lcsb.uni.lu/e/compound/3037629
  10. Chakraborty, S., et al. (2021). Metabolic profiling of kratom alkaloid extracts. Drug Testing and Analysis, Wiley. https://pubmed.ncbi.nlm.nih.gov/19902190/
  11. Ellis, C. R., Racz, R., Kruhlak, N. L., Kim, M. T., Zakharov, A. V., Southall, N., & Hawkins, E. G. (2020). Evaluating kratom alkaloids using PHASE: Opioid receptor binding of mitragynine, 7-hydroxymitragynine, and related compounds. PLOS ONE, 15(2), e0229646. https://doi.org/10.1371/journal.pone.0229646
  12. León, F., Habib, E., Trojahn, T., Adkins, J. E., Furr, E. B., McCurdy, C. R., & Cutler, S. J. (2021). Phytochemical characterization of Mitragyna speciosa (Kratom) and evaluation of serotonergic activity of its alkaloids. Frontiers in Pharmacology, 12, 640236. https://doi.org/10.3389/fphar.2021.640236
  13. World Health Organization. (2021). Review of kratom and its alkaloids by the Expert Committee on Drug Dependence. WHO Technical Report. https://www.who.int/medicines/access/controlled-substances/ecdd_44_meeting/en/
  14. U.S. Food and Drug Administration. (2025). What you need to know about kratom. FDA Consumer Updates. https://www.fda.gov/consumers/consumer-updates/what-you-need-know-about-kratom