ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Multifaceted Modulation of Human Opioid Receptors by Kratom Alkaloids: Binding Affinity, Functional Selectivity, and Allosteric Activity
Provisionally accepted
Scott Hemby1*
M. Rangel-Grimaldo2,3
Scot McIntosh1J. Zheng1
Laura Flores-Bocanegra3
Tyler Nelson Graf2R.A. Coover4N. H. Oberlies2- 1Basic Pharmaceutical Sciences, High Point University, High Point, NC, United States
- 2UNC Greensboro, Greensboro, United States
- 3Universidad Nacional Autonoma de Mexico Instituto de Quimica, Mexico City, Mexico
- 4US Food and Drug Administration, Silver Spring, United States
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Kratom (Mitragyna speciosa) contains over 50 alkaloids, yet the pharmacological activity of most remains poorly defined, limiting our understanding of its therapeutic potential and safety profile. In this study, we conducted a comprehensive evaluation of both indole and oxindole alkaloids at human mu-, kappa-, and delta-opioid receptors (hMOR, hKOR, hDOR), integrating radioligand binding, cAMP inhibition, β-arrestin2 recruitment, [³⁵S]GTPγS assays, and molecular docking. While the activity of major alkaloids like mitragynine and 7-hydroxymitragynine is well documented, we report detailed functional and structural characterization of lesser-known kratom alkaloids, including epiallo-isopaynantheine, isopaynantheine, mitraciliatine, and isospeciofoline. These compounds exhibited diverse receptor selectivity and functional profiles, ranging from G protein-biased agonism to mixed MOR antagonism/KOR agonism. Notably, speciophylline demonstrated positive allosteric modulation at hMOR without direct orthosteric binding - a mechanism not previously demonstrated experimentally for kratom alkaloids at human opioid receptors. Several oxindole alkaloids showed potent hMOR agonism with minimal β-arrestin2 recruitment, representing an extreme G-protein signaling bias that distinguishes them from classical opioids. Structure-activity analysis identified conserved pharmacophoric elements at C15 and C20 that govern receptor affinity and functional profile across both indole and oxindole scaffolds. This systematic characterization at human opioid receptors reveals a pharmacologically diverse and structurally tunable class of natural products with potential as templates for developing opioid analgesics with improved therapeutic profiles.
Keywords: 7-hydroxymitragynine, functional selectivity, Kratom, Mitragyna speciosa, mitragynine, opioid receptor signaling, positive allosteric modulation, structure activity relationship
Received: 09 Dec 2025; Accepted: 28 Jan 2026.
Copyright: © 2026 Hemby, Rangel-Grimaldo, McIntosh, Zheng, Flores-Bocanegra, Graf, Coover and Oberlies. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Scott Hemby
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