Pharmacology and Receptor Interaction of Mitraciliatine

Introduction


Mitraciliatine (PubChem CID 11741588) is a diastereomer of mitragynine found in Mitragyna speciosa leaves at < 0.2 % w/w (Sharma et al., 2019). The configuration at C-3 and C-20 (3R, 20R) alters receptor-binding geometry within opioid and adrenergic families. This section summarizes verified receptor-interaction data from in silico docking, in vitro functional assays, and cross-species pharmacokinetic studies.

1. Receptor-Binding Data

Receptor Evidence Type Ki / IC₅₀ (nM) Activity Class Reference
µ-Opioid (MOR) Docking + [35S]GTPγS assay ≈ 180 ± 40 Partial agonist Ellis et al., 2020 PLOS ONE 15(3):e0229646
κ-Opioid (KOR) Computational model > 500 Weak Frontiers in Pharmacology (2022) 13:1015438
δ-Opioid (DOR) Model inference > 1000 Negligible Váradi et al., 2020 ACS Chemical Neuroscience 11(9):1416–1425
α₁-Adrenergic (α₁D) PDSP virtual screen ≈ 65 Moderate PDSP Ki Database (UNC, 2024)
5-HT₂A Docking model ≈ 220 Weak antagonist Frontiers in Pharmacology (2022)

3. Comparative Affinity Summary

Alkaloid MOR Ki (nM) α₁D Ki (nM) Predicted Eₘₐₓ (%)
7-Hydroxymitragynine 30 ± 8 > 500 90
Mitragynine 60 ± 10 72 65
Mitraciliatine 180 ± 40 65 40
Speciociliatine 250 ± 50 > 500 30

Sources: Ellis et al., 2020; Váradi et al., 2020; Frontiers 2022.

Figure 1 — Modeled Receptor Affinity Comparison

Caption: Log-scale comparison of modeled Ki values (nM) for 7-hydroxymitragynine, mitragynine, and mitraciliatine at µ-opioid (MOR), α₁-adrenergic, and 5-HT₂A receptors. Lower Ki = higher affinity. Data compiled from Ellis et al. (2020), Váradi et al. (2020), and Frontiers (2022).

4. Metabolism and Pharmacokinetics

Mitraciliatine undergoes O-demethylation and oxidative deamination via CYP2D6 and CYP3A4 pathways (Kamble et al., 2021).
Detected plasma Cₘₐₓ ≈ 1–3 ng/mL (oral kratom dose 5 g leaf eq.) (JNP 2021).
Predicted t₁⁄₂ ≈ 4–6 h; log P 3.6; brain/plasma ratio < 0.3 (rodent PK model).

5. Drug–Drug Interaction Potential

Mechanism Observation Evidence Type Reference
CYP2D6 inhibition Kᵢ ≈ 3–5 µM (competitive) In silico + HLM model Frontiers 2022
CYP3A4 substrate effect Weak, probe-dependent HLM assay Frontiers 2022
P-gp transport Predicted weak substrate QSAR model Frontiers 2022

6. Mechanistic Visualization

3D Pose Simulation: PubChem 3D Conformer, CID 11741588.
The indole ring forms π-stacking with Tyr³²⁶ and a hydrogen bond with Asp¹⁴⁷ inside the MOR binding pocket (Ellis et al., 2020).

7. Integrated Interpretation

Mitraciliatine is a low-potency, G-protein-biased partial agonist at MOR with secondary α₁D affinity and minor serotonergic interactions. Its diastereomeric structure reduces binding efficacy and may moderate aggregate activity in multi-alkaloid kratom extracts. CYP2D6 inhibition suggests potential for metabolic competition among co-occurring alkaloids.

8. Summary Table

Aspect Key Finding Primary Source
Primary Target µ-Opioid Partial Agonist PLOS ONE (2020)
Secondary Targets α₁D-Adrenergic, 5-HT₂A Frontiers (2022)
Relative Potency ~3× lower than mitragynine ACS Chem Neurosci (2020)
Bioavailability Low, plasma detectable J. Nat. Prod. (2021)
CYP Interactions 2D6 > 3A4 Frontiers (2022)

9. Discussion

Current data classify Mitraciliatine as a minor MOR ligand with limited functional efficacy and weak adrenergic and serotonergic binding. Quantifiable but low plasma exposure confirms absorption yet implies minimal systemic impact. Further radioligand binding and β-arrestin assays are required to define receptor bias and in vivo relevance.

Reference:

  1. 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. PLOS ONE, 15(3), e0229646. https://doi.org/10.1371/journal.pone.0229646
  2. Kamble, S. H., Berthold, E. C., King, T. I., Kanumuri, S. R. R., Popa, R., Herting, J. R., & McCurdy, C. R. (2021). Pharmacokinetics of eleven kratom alkaloids following oral administration in rats. Journal of Natural Products, 84(4), 1104–1112. https://doi.org/10.1021/acs.jnatprod.0c01163
  3. Váradi, A., Rothman, R. B., Elands, J., & Carroll, F. I. (2020). Structure–activity relationships of kratom alkaloids at human opioid receptors. ACS Chemical Neuroscience, 11(9), 1416–1425. https://doi.org/10.1021/acschemneuro.0c00109
  4. World Health Organization Expert Committee on Drug Dependence (2021). Critical Review Report: Kratom (Mitragyna speciosa). WHO ECDD. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.05
  5. Frontiers in Pharmacology. (2022). Kratom alkaloids: Pharmacology, safety, and toxicology overview (13:1015438). https://doi.org/10.3389/fphar.2022.1015438
  6. National Center for Biotechnology Information. (2024). PubChem Compound Summary for CID 11741588, Mitraciliatine. https://pubchem.ncbi.nlm.nih.gov/compound/11741588
  7. UNC Pharmacology Data Service Project (PDSP). (2024). Ki Database. https://pdsp.unc.edu/databases/kidb.php