Paynantheine & Opioid Receptors

Paynantheine and the Opioid Receptor System


While Mitragynine and 7-Hydroxymitragynine are known opioid receptor agonists, Paynantheine shows antagonistic activity at opioid receptors. Its weaker receptor interactions highlight its distinct pharmacological contribution compared to kratom’s primary alkaloids.

Binding Affinity at Opioid Receptors

Studies using radioligand binding assays have demonstrated that Paynantheine exhibits measurable but modest interactions with opioid receptors:

Receptor Type Activity Notes Source
μ-Opioid Receptor (MOR) Antagonist (competitive) Prevents agonist activity of Mitragynine/7-OH PMC – Pharmacological Characterization [1]
κ-Opioid Receptor (KOR) Antagonist (competitive) Reduces KOR agonist activity PMC – Binding Assays [2]
δ-Opioid Receptor (DOR) Weak/Negligible Minimal binding observed PubMed – Receptor Affinity [3]

Mechanism of Antagonism

  • Paynantheine does not activate MOR or KOR but instead competes for binding sites, reducing the effects of agonist alkaloids.
  • This antagonistic effect may function as a natural “balancing” mechanism within kratom, moderating the stronger opioid activity of Mitragynine and 7-Hydroxymitragynine.
  • Its role resembles a pharmacological buffer, potentially lowering the risk of opioid-like adverse effects.

Comparative Potency

Experimental data show that Paynantheine’s opioid receptor effects are significantly weaker than kratom’s primary agonists:

Alkaloid MOR Activity KOR Activity Overall Opioid Potency
Mitragynine Partial agonist Weak agonist High
7-Hydroxymitragynine Strong agonist Strong agonist Very high
Paynantheine Competitive antagonist Competitive antagonist Very low

Implications

  • Alkaloid antagonism may reduce the addictive potential of botanical compounds compared to single-target agonists.
  • It contributes to botanical polypharmacology, showing that effects cannot be explained by individual compounds alone.
  • By acting as a receptor modulator, certain alkaloids may play a role in the unique safety and efficacy profiles of botanical preparations.

Summary

  • Classification: Indole alkaloid compounds with complex molecular structures.
  • Occurrence: Secondary metabolites found in various percentages within botanical samples.
  • Analysis: HPLC and LC-MS methods validated with certified reference standards.
  • Pharmacology: Receptor binding profiles including serotonin and opioid receptor interactions.
  • Function: Contributes to modulatory effects in botanical preparations through multi-target mechanisms.

Reference Link:

  1. 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 and opioid activity of its alkaloids. Frontiers in Pharmacology, 12, 640236. https://doi.org/10.3389/fphar.2021.640236
  2. Váradi, A., Marrone, G. F., Palmer, T. C., Narayan, A., Szabó, M. R., Le Rouzic, V., … & Majumdar, S. (2016). Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with μ agonism and δ antagonism, unusual binding interactions, and favorable abuse liability profiles. Journal of Medicinal Chemistry, 59(18), 8381–8397. https://doi.org/10.1021/acs.jmedchem.6b00748
  3. Kruegel, A. C., & Grundmann, O. (2018). The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology, 134, 108–120. https://doi.org/10.1016/j.neuropharm.2017.08.026
  4. 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