Corynantheidine vs Other Kratom Alkaloids

Comparative Analysis Of Corynantheidine With Other Kratom Alkaloids (Occurrence, Receptor Pharmacology, Safety Context)

Compare corynantheidine with major kratom alkaloids, mitragynine, 7-hydroxymitragynine, paynantheine, speciociliatine, and speciogynine, using validated occurrence data and peer-reviewed receptor/pharmacology results. Figures and download links are embedded.

Data sources used

Occurrence/quantitation (plant & products): validated UPLC–MS/MS ten-alkaloid method; ranges across leaves, extracts, teas, finished products [1].
US product survey (N≈341; 10 alkaloids quantified): mean levels across finished products; screen against non-alkaloid adulterants [2].
Chemotypes/variability (UPLC-HRMS across plants & products): distinct alkaloid profiles (affects minor-alkaloid levels) [3].
Receptor binding/function: human MOR/KOR and α1D binding; MOR signaling and β-arrestin; in vivo antinociception [4].
Serotonin receptor data (paynantheine comparator): 5-HT₁A activity [5].
Potent MOR comparator (7-hydroxymitragynine): antinociception and context [6].

Occurrence (leaves, extracts, commercial products)

Validated UPLC–MS/MS ranges across matrices (percent of product mass, % w/w) from the ten-alkaloid QC panel:

Mitragynine: 0.7–38.7
Paynantheine: 0.3–12.8
Speciociliatine: 0.4–12.3
Speciogynine: 0.1–5.3
7-Hydroxymitragynine: 0.01–2.8
Corynantheidine: 0.01–2.8 (minor constituent) [7]

Extensive U.S. product survey (2025) reported mean levels of minor alkaloids (including corynantheidine) <0.05% w/w in finished products; no non-alkaloid adulterants detected in the screened set [8].

Implication: Corynantheidine occurs at low levels relative to mitragynine; batch-to-batch variability is expected due to chemotypes and processing [9].

Receptor pharmacology

Binding (human targets; Kᵢ, nM)

Corynantheidine: MOR 118 ± 12; KOR 1,910 ± 50; α₁D 41.7 ± 4.7. Affinity pattern: α₁D ≤ MOR ≪ KOR [10].
Mitragynine (comparator): MOR 161; KOR 198; α₁D 5,480 [11].

Functional signaling and bias

Functional Pharmacology (human and in vivo data)

Corynantheidine: partial hMOR agonist (BRET Gi-1 EC₅₀ ≈ 67 nM; E_max ≈ 37% of DAMGO); β-arrestin-2 not detected (<20%). In vivo, MOR-dependent antinociception after i.c.v. dosing confirms central MOR engagement with partial efficacy [12].
Mitragynine: low-efficacy MOR agonist (context across reviews/primary datasets) [13].
7-Hydroxymitragynine: potent MOR agonist with strong antinociception; contribution to mitragynine’s effects in vivo is context-dependent (conversion/PK) [14].
Paynantheine: strongest evidence is serotonin 5-HT₁A activity; opioid agonism weak/absent in primary datasets [15].

Comparative interpretation

Comparative Target and Functional Profiles

Target preference: Corynantheidine exhibits high α1D binding and moderate MOR binding with weak KOR binding, whereas mitragynine shows stronger KOR relative to corynantheidine and much weaker α1D. This is consistent with C-9 demethoxy substitution (mitragynine → corynantheidine) altering KOR interactions and favoring α1D [16].
Functional profile: Corynantheidine’s partial MOR agonism with minimal β-arrestin recruitment differs from 7-hydroxymitragynine’s potent MOR agonism; this divergence is relevant to analgesic efficacy and tolerability hypotheses but requires clinical verification [17].
Serotonergic comparator: paynantheine adds a non-opioid serotonergic dimension (5-HT₁A), emphasizing polypharmacology beyond MOR/KOR [18].

Safety/toxicology context

Risk & Variability Context

7-Hydroxymitragynine: the most opioid-like and potent MOR agonist among the listed alkaloids (preclinical), warranting the greatest caution [19].
Corynantheidine: partial MOR agonism with no β-arrestin-2 signal in vitro; limited human data [20].
Population/product variability: chemotypes explain differing minor-alkaloid exposures across products [21].

Note: Regulatory/health-risk summaries for “kratom” overall are covered in independent assessments (e.g., WHO ECDD review); this subarticle centers on compound-level pharmacology and occurrence. (If needed, cite the WHO report alongside this section.)

Methods

Reporting Requirements

Matrix and preparation (leaf/extract/tea/product) and extraction conditions.
LC–MS/MS platform, column, gradient, MRM transitions, calibration range, LLOQ; internal standard.
QC acceptance criteria (accuracy/precision) referencing the validated method you used.

Summary

Affinity and Functional Profile

Corynantheidine shows high α₁D-adrenergic affinity (Kᵢ = 41.7 ± 4.7 nM) and moderate μ-opioid (MOR) affinity (Kᵢ = 118 ± 12 nM), with weak κ-opioid (KOR) binding (Kᵢ = 1.91 µM) and no quantified δ-opioid (DOR) binding under screening cutoffs [22, 23]. Off-target screening also reports α₂A (Kᵢ ≈ 74 nM) and NMDA (Kᵢ ≈ 83 nM) interactions (binding only). Functionally, at human MOR, corynantheidine behaves as a partial agonist (EC₅₀ = 67.2 nM; Emax = 37.2% vs. DAMGO = 100%) with no β-arrestin-2 recruitment detected at MOR/KOR/DOR; mouse MOR assays and MOR-dependent antinociception after i.c.v. dosing corroborate partial efficacy in vivo. Selectivity indices calculated from Kᵢ values indicate α₁D > MOR ≫ KOR (MOR/α₁D ≈ 2.83; KOR/α₁D ≈ 45.8) [25]. Relative to mitragynine, C-9 demethoxylation (mitragynine → corynantheidine) maintains MOR, weakens KOR, and increases α₁D affinity ~131×, consistent with docking rationales (e.g., loss of a methoxy-mediated contact at KOR). Serotonergic data for corynantheidine remain unreported in primary assays (unlike other kratom indoles), and direct α₁D functional testing plus human PK are still needed to connect in-vitro potency to achievable exposures; receptor background and comparator potencies can be cross-checked in IUPHAR/BPS resources.