# Appendix D: Receptor and Target Catalogue

This appendix preserves the detailed receptor synthesis used for the pharmacodynamics page. The standard is functional activation at plausibly relevant potency, not docking or binding alone.

## Functionally activated receptors with the strongest support

| Receptor | Demonstrated activators among characterized kratom alkaloids/metabolites | Interpretation |
|---|---|---|
| **Mu-opioid receptor (MOR)** | 7-OH, mitragynine, mitragynine pseudoindoxyl, 9-O-demethylmitragynine, speciociliatine, paynantheine, speciogynine, several oxindoles/minor alkaloids | Dominant clinically relevant system. 7-OH is high potency with assay- and receptor-reserve-dependent efficacy. [E12, E15-E16, E18] |
| **Kappa-opioid receptor (KOR)** | Compound- and assay-dependent activation by 7-OH, mitragynine, speciociliatine, mitraciliatine, isopaynantheine, and MG-N-oxide | Secondary and inconsistent across assay systems; do not reduce to one universal agonist/antagonist label. [E12, E15] |
| **Delta-opioid receptor (DOR)** | Principally 7-OH in recent functional systems; additional activity varies by compound | Functional activation is supported in vitro; clinical contribution remains uncertain. [E12] |
| **5-HT1A** | 9-O-desmethylspeciogynine and 9-O-desmethylpaynantheine | Strong functional laboratory signal for metabolites of minor botanical alkaloids; not proof that purified 7-OH is serotonergic. [E13] |
| **alpha1A-adrenergic** | Mitragynine | Low-potency partial agonism; possible contribution to botanical autonomic/stimulant features. [E14] |

## Binding or modulation that should not be mislabeled as activation

- Mitragynine behaves as an **alpha2A antagonist**, not a direct alpha2 agonist, in current functional work. [E14]
- Speciogynine and paynantheine bind several serotonin receptors, but binding is not synonymous with agonism; their O-desmethyl metabolites show 5-HT1A agonism and 5-HT2B inverse-agonist behavior. [E13]
- Dopamine-receptor docking or displacement is not proof of functional activation.
- CB1 mediation of mitragynine analgesia has not been convincingly demonstrated.
- Speciophylline has been described as a positive allosteric modulator of MOR rather than a direct agonist. [E12]
- There is no recognized "gamma opioid receptor." The canonical opioid receptors are MOR, KOR, DOR, and NOP/ORL1; the gamma symbol in an older teaching slide is not a receptor category for kratom pharmacology.

## Preferred 7-OH wording

> 7-OH is a high-potency mu-opioid receptor agonist with strongly G-protein-favoring signaling and assay-dependent intrinsic efficacy. It behaves as a partial agonist in some low-reserve systems and approaches full functional efficacy in others. Secondary KOR and DOR activity is assay-dependent, and the human clinical importance of those targets remains uncertain.