Isopaynantheine: Secondary Kratom Alkaloid

Isopaynantheine is a minor monoterpenoid indole alkaloid occurring in Mitragyna speciosa (kratom) at low abundance. Structurally related to paynantheine and mitragynine, it has emerged as a mechanistically important component of the kratom alkaloid profile due to its mu-opioid receptor (MOR) antagonism and kappa-opioid receptor (KOR) G-protein–biased agonism. Analytical studies confirm its presence in young plants, mature leaves, and commercial products, and validated LC–MS/MS platforms support its detection in biological matrices. Preclinical studies describe antinociceptive activity mediated predominantly by KOR, with minimal β-arrestin-2 recruitment and no clear respiratory depression in animal models under tested conditions. Metabolism studies in rats and humans reveal phase I and II metabolites similar to other corynanthe-type alkaloids. No human pharmacokinetic data for isolated isopaynantheine exist, and its clinical toxicological relevance remains undefined. This review compiles available evidence on chemistry, occurrence, receptor pharmacology, metabolism, analytical methodologies, and safety considerations, identifying major research gaps for future investigation.

Key Findings

Minor indole alkaloid in kratom. Isopaynantheine is a low-abundance monoterpenoid indole alkaloid in Mitragyna speciosa, typically representing less than 1% of total alkaloid content in mature leaves and commercial products. However, it may be relatively enriched in young plants and certain chemotypes [1].
Confirmed occurrence in plants and products. It has been reported in authenticated kratom leaf material, young plants, and commercial products, and has also been detected in at least one additional Mitragyna species [2].
Distinct opioid receptor profile. In vitro receptor profiling using BRET-based assays shows that isopaynantheine lacks measurable G-protein agonism at human MOR, acts as a MOR antagonist, and functions as a submicromolar KOR agonist with minimal β-arrestin-2 recruitment [3].
KOR-mediated antinociception. As observed in vivo in rodent models, its analgesic-like effects are blocked by KOR-selective antagonists, demonstrating that they are KOR-dependent rather than MOR-driven.
Metabolic fate paralleling major indole alkaloids. Metabolism studies in rat and human urine demonstrate O-demethylation, oxidation, dehydrogenation, and subsequent conjugation (glucuronidation and sulfation), mirroring the biotransformation pathways of mitragynine and related diastereomers [4].
Analytical detectability at low levels. Validated LC–MS/MS and LC–HRMS methods detect isopaynantheine at low ng/mL in biological samples and low w/w percentages in plant extracts, supporting pharmacokinetic, forensic, and quality-control applications [5].
Concentration variability across chemotypes and processing conditions. Cultivation and product surveys show substantial variability in isopaynantheine levels across genotypes, geographic origins, and post-harvest processing regimes [6].
Limited safety and clinical data. Preclinical evidence suggests KOR-mediated antinociception without obvious respiratory depression in animals, but no human PK, safety, or clinical DDI studies focused specifically on isopaynantheine have been published [7].

Introduction

Corynanthe-type monoterpenoid indole alkaloid. Isopaynantheine is a corynanthe-type monoterpenoid indole alkaloid found in Mitragyna speciosa and related Mitragyna species [8]. It is a diastereomer of mitragynine and paynantheine, sharing the molecular formula C₂₃H₂₈N₂O₄ but differing in stereochemistry at specific chiral centers. Its presence has been confirmed in kratom leaf material, young plants, and commercial kratom products.
Chemical classification. Chemically, isopaynantheine belongs to the group of 9-methoxy corynanthe-type alkaloids, characterized by a vinyl side chain at C-20, similar to paynantheine [9].
Distinct pharmacological profile. Although present at much lower concentrations than mitragynine, recent work identifies isopaynantheine as a KOR-biased agonist and MOR antagonist with minimal β-arrestin-2 recruitment, distinguishing it from major kratom alkaloids that display primarily MOR partial agonism. As kratom research increasingly considers contributions from minor indole and oxindole alkaloids, isopaynantheine has emerged as an important candidate for mechanistic and safety-focused studies [10].

Objectives

This paper reviews the current state of knowledge on isopaynantheine with the following aims:

Summarize chemical identity and structural classification. The paper outlines the chemical identity of isopaynantheine and its classification as a corynanthe-type monoterpenoid indole alkaloid [11].
Describe natural occurrence and abundance. It reviews the presence of isopaynantheine in kratom leaves, young plants, and commercial kratom products, highlighting its typically low abundance [12].
Evaluate receptor pharmacology. The paper examines activity at opioid and selected non-opioid receptors, with emphasis on KOR-biased signaling and MOR antagonism [13].
Review metabolism and pharmacokinetic context. It summarizes findings from preclinical and translational studies relating to metabolism, biotransformation pathways, and broader PK considerations [14].
Compile analytical methods. Analytical techniques for quantifying isopaynantheine in biological matrices and plant materials are discussed, including LC–MS/MS and HRMS approaches [15].
Assess safety and DDI implications. The review considers safety, toxicological findings, and potential drug–drug interaction risks based on available in vitro, in vivo, and computational modeling data for kratom alkaloids [14].

Methods

Literature Search Strategy

Structured multi-database search. A systematic search was conducted in PubMed, Web of Science, Scopus, and Google Scholar using combinations of the terms “isopaynantheine,” “ISO-PAY,” “kratom alkaloid,” “minor indole alkaloid,” “receptor pharmacology,” “metabolism,” “LC–MS/MS,” and “LC–HRMS” up to November 2025 [15].
Supplemental manual screening. Reference lists from relevant analytical chemistry, pharmacology, and natural products studies were reviewed to identify additional sources.

Inclusion / Exclusion Criteria

Included:

Peer-reviewed experimental papers with data on isopaynantheine (chemistry, occurrence, analytics, pharmacology, metabolism)
Reviews and methods papers explicitly discussing or contextualizing isopaynantheine
High-quality chemical database identifiers (PubChem, NCATS Inxight)

Excluded:

Non-peer-reviewed or unverifiable content
Studies failing to distinguish isopaynantheine from structurally similar alkaloids
Redundant, superseded, or non-specific reports

Data Extraction & Quality Assessment

For each eligible publication, the following data were extracted:

Chemistry/Identifiers: CAS, PubChem CID, molecular formula, classification
Occurrence: Concentration range in plant material and commercial products
Pharmacology: Receptor type, EC₅₀, Emax, signaling bias, antagonist activity
Metabolism & PK: Metabolite structures, pathways, matrices (rat vs human urine/plasma)
Analytical Methods: Instrument type, matrix, LOQ, validation parameters (precision, accuracy)
Safety/DDI: Toxicity endpoints, enzyme/transporter interactions (direct or inferred)

Study quality was assessed qualitatively by:

Use of validated assays and proper controls
Detailed reporting of methods and experimental conditions
Replication or independent confirmation (where available)

Results

Chemistry & Identifiers

Isopaynantheine is a corynanthe-type monoterpenoid indole alkaloid with the same molecular formula (C₂₃H₂₈N₂O₄) as mitragynine and paynantheine but with a distinct stereochemical configuration.

Parameter	Value
Preferred name	Isopaynantheine [16]
CAS Registry Number	22032-51-5 [17]
PubChem CID	101804033 [18]
Molecular formula	C₂₃H₂₈N₂O₄ [19]
Molecular weight	396.48 g/mol [20]
Structural class	Monoterpenoid indole alkaloid (corynanthe-type) [21]

Table 1. Selected chemical identifiers for isopaynantheine

Natural Occurrence & Quantification

Young plants: Early work on young kratom plants and C-3Hβ-configured indole alkaloids identified isopaynantheine among key constituents alongside mitraciliatine and isocorynantheidine [22].
Mature leaves and commercial products: Comprehensive surveys of kratom materials show isopaynantheine as a minor constituent, often <1% of total alkaloid content, though product-to-product variability is considerable [23].
Enriched minor-alkaloid fractions: In a study focusing on isolated minor indole alkaloids, isopaynantheine accounted for ~0.03% of total alkaloid mass in an enriched fraction [24].

Receptor Pharmacology

Chakraborty et al. provide the primary dataset for isopaynantheine’s opioid receptor pharmacology, using BRET-based assays at human MOR, KOR, and DOR [25].

µ-Opioid Receptor (MOR)

No significant G-protein agonism (Emax < 20% in Gi-1 BRET) [26].
In antagonist mode, isopaynantheine displays micromolar potency (EC₅₀ ≈ 1.26 µM) and blocks MOR signaling induced by a reference agonist [27].

κ-Opioid Receptor (KOR)

G-protein agonist with EC₅₀ ≈ 560 nM and Emax ≈ 80% of the standard agonist [28].
β-arrestin-2 recruitment is minimal (<20% Emax), indicating G-protein–biased KOR agonism.

δ-Opioid Receptor (DOR)

No meaningful agonist or β-arrestin signals at tested concentrations.

Analytical Methods

UPLC–MS/MS (triple quadrupole): Quantification of major and minor alkaloids in plasma, urine, and plant extracts with LOQs in the low-ng/mL range [29].
Example LC–MS/MS method used in PK and DDI studies of kratom products includes isopaynantheine among analytes [30].
UPLC–HRMS / LC–QTOF: High-resolution profiling of 14 or more indole and oxindole alkaloids in U.S.-grown plants and products [31].
LC–LIT–MS: Philipp et al. used LC–linear ion trap MS for structural elucidation of isopaynantheine metabolites in rat and human urine [32].

Safety, Toxicology & Potential Drug–Drug Interactions

Antinociception without obvious respiratory depression: In mouse assays, isopaynantheine produced KOR-dependent antinociception, and under the reported experimental conditions, no substantial respiratory depression was noted [33].
Lack of detailed toxicological endpoints: Systematic evaluation of cardiovascular, respiratory, and CNS toxicity has not been conducted for the isolated compound.
Broader DDI and safety assessments of kratom alkaloids: Multiple indole alkaloids can inhibit CYP enzymes—particularly CYP3A and CYP2D6—and may interact with drug transporters. Most enzyme-inhibition studies have focused on mitragynine and selected minor alkaloids; isopaynantheine is usually grouped within the broader “minor indole alkaloid” pool rather than tested individually. Tanna and Paine (2023) review kratom’s clinical DDI potential using mechanistic and PBPK modeling, highlighting the role of multiple alkaloids in CYP3A-mediated interactions [34].
No human DDI or safety studies: At present, no clinical safety or interaction studies have examined isopaynantheine directly. Any risk assessment must therefore extrapolate from:
- its low abundance in most products,
- its KOR/MOR pharmacological profile,
- broader kratom DDI evidence involving the whole alkaloid mixture.

Discussion

Isopaynantheine is a quantitatively minor but mechanistically notable kratom alkaloid. Its combination of MOR antagonism and G-protein–biased KOR agonism contrasts with the MOR-focused partial agonism of mitragynine and 7-hydroxymitragynine. This distinct signaling profile positions isopaynantheine as a useful tool compound for exploring biased KOR signaling and for understanding how minor kratom alkaloids may modulate the net pharmacodynamic output of kratom preparations.

Metabolism data from rats and humans demonstrate that isopaynantheine follows similar biotransformation routes as mitragynine and its diastereomers, including O-demethylation and conjugation pathways, confirming that it contributes to the diverse metabolite pattern seen in biological samples from kratom users. Analytical methods, especially UPLC–MS/MS and UPLC–HRMS, now routinely include isopaynantheine in multianalyte alkaloid panels, allowing better characterization of its concentration across plant materials and finished products.

However, significant data gaps remain:

No human pharmacokinetic data for isolated isopaynantheine
No targeted human safety or DDI studies
Inadequate toxicological profiling beyond limited preclinical observations
No quantitative modeling of its contribution relative to major alkaloids in typical kratom exposure scenarios

Future work should prioritize:

Human PK studies with isolated isopaynantheine or standardized kratom preparations that quantify its plasma levels.
In vitro enzyme and transporter interaction assays specifically testing isopaynantheine’s inhibition and substrate potential.
Translational modeling integrating its pharmacology, abundance, and metabolism into whole-kratom risk assessments.

Until such data emerge, isopaynantheine is best viewed as a mechanistic contributor and potential modulator of kratom’s pharmacological ensemble, rather than a fully characterized clinical actor.