Paynantheine

Paynantheine is one of the most abundant minor alkaloids in Mitragyna speciosa (kratom), typically accounting for 10–15% of total alkaloid content. It functions primarily as a competitive antagonist at μ- and κ-opioid receptors while showing strong serotonergic activity at 5-HT₁A receptors (Ki ~32 nM).
Comparative analysis suggests Paynantheine’s 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. It is metabolized via CYP450 enzymes, raising potential for drug interactions.
Future research should focus on controlled pharmacological assays, metabolic characterization, and clinical studies to evaluate therapeutic applications in anxiety, depression, and neuropathic pain.

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.

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.

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)

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 Å²

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]

Figure 1. Paynantheine receptor binding affinities

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

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

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

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:
1. Functions more as a modulator than a direct psychoactive driver.
2. By antagonizing μ- and κ-opioid receptors, it may buffer kratom’s overall opioid load, reducing overstimulation risk.
3. 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.

Pharmacological Role: Paynantheine acts as a competitive antagonist at μ- and κ-opioid receptors while showing strong affinity for 5-HT₁A, making it a serotonergic and modulatory compound rather than a direct opioid driver.
Safety Profile: Evidence suggests a favorable profile with lower toxicity risk compared to Mitragynine and 7-Hydroxymitragynine.
Knowledge Gaps: Limited toxicological data and absence of human clinical trials restrict definitive conclusions.
Future Potential: Paynantheine may serve as a key balancing alkaloid in kratom, with promising implications for mood regulation, analgesic balance, and therapeutic exploration.