Corynantheidine: Adrenergic & Opioid Pharmacology

Adrenergic and Opioid Receptor Pharmacology

Receptor Pharmacology & Structural Context

This section compiles experimentally verified receptor binding (Ki), functional signaling, and structural context for corynantheidine, with emphasis on adrenergic (α1/α2) and opioid (μ/κ/δ) targets. Primary data are drawn from radioligand binding and functional assays (e.g., BRET, [35S]GTPγS), while target background and comparator information come from curated pharmacology resources. Where no direct data exist for a target (for example, 5-HT receptors and corynantheidine), that gap is stated explicitly. [1]

Binding affinities (Kᵢ) at adrenergic and opioid receptors

Receptor Binding Data
  • α1D-adrenergic (human, CHO): Ki = 41.7 ± 4.7 nM. Radioligand competition with [³H]prazosin; Eurofins panel. Highest adrenergic affinity among kratom indole alkaloids, 131-fold higher than mitragynine at α1D [2].
  • μ-opioid (MOR; human, HEK): Ki = 118 ± 12 nM [3].
  • κ-opioid (KOR; rat RBL binding, human function): Ki = 1910 ± 50 nM (much weaker than MOR) [4].
  • δ-opioid (DOR): No specific Ki reported (insufficient displacement at screening) [5].
  • α2A-adrenergic (human): Off-target screening shows Ki ≈ 74 nM (PDSP panel) [6].
  • NMDA receptor (human): Off-target Ki ≈ 83 nM [7].
  • Selectivity indices: MOR/α1D ≈ 2.83; KOR/α1D ≈ 45.8 → corynantheidine prefers α1D > MOR ≫ KOR under the binding conditions used [8].

Target context: α1D is a Gq/11-coupled receptor involved in vascular and prostatic smooth muscle contraction; prazosin and doxazosin are sub-nanomolar benchmarks at α1D (pKi ~9) [9].

Functional signaling

Opioid Receptors
  • hMOR (BRET Gi-1): Corynantheidine is a partial agonist with EC50 = 67.2 nM and Emax = 37.2% vs DAMGO (100%). No β-arrestin-2 recruitment detected (<20%) at MOR. These data align with mMOR [³⁵S]GTPγS assays (partial agonist; Emax = 74%) [10].
  • hKOR and hDOR: No measurable Gi signaling and no β-arrestin-2 recruitment (<20%) for corynantheidine at the tested ranges [11].

Adrenergic Receptors

Functional (agonist/antagonist) readouts for α₁D were not reported in the same studies; however, the binding Kᵢ pattern and the α₁D pharmacology suggest antagonist-like behavior would be consistent with the structural class (yohimbine-like) and with α₁ antagonists’ canonical effects. This is a cautious inference; direct functional α₁D data for corynantheidine are not yet published in the sources cited here.

In Vivo Nociception

Mouse antinociception (i.c.v., warm-water tail withdrawal): corynantheidine produced a ceiling ~50% MPE, and the effect was MOR-dependent in MOR-KO mice, consistent with MOR partial agonism and absence of β-arrestin recruitment [12].

Structure–Activity Context (SAR)

C-9 methoxy removal (mitragynine → corynantheidine) does not reduce MOR binding but reduces KOR affinity; docking attributes this to loss of a methoxy–Thr111 interaction in KOR and steric/hydrogen-bonding differences across subpockets [13]. Earlier docking/structure work on mitragynine-template ligands supports key residue roles (e.g., Trp293, His297, Gln124, Tyr128) that rationalize MOR/KOR differences [14].

Serotonergic Evidence

For corynantheidine, no validated 5-HT receptor binding/function has been reported in the sources above. (Recent serotonergic assays on kratom alkaloids emphasized other congeners—e.g., speciogynine, mitragynine—rather than corynantheidine.) Any serotonergic role for corynantheidine remains unconfirmed in peer-reviewed primary data [15].

Evidence Limits and Requirements
  • Serotonergic: No validated 5-HT binding/functional data for corynantheidine in the primary sources; serotonergic activity is established for other kratom indoles (e.g., paynantheine at 5-HT₁A/5-HT₂B), not for corynantheidine. Do not generalize across congeners [16].
  • Adrenergic function: α₁D binding is robust; functional α₁D (agonism/antagonism) for corynantheidine is not yet published in the cited datasets; inference of α₁D antagonism remains a hypothesis until tested [17].
  • Species/assay: hMOR (BRET) vs mMOR ([³⁵S]GTPγS) differ in apparent efficacy; report species, cell line, and assay for all comparisons [18].
Practical Implications

The profile differs from potent MOR agonists: partial MOR agonism, no β-arrestin-2, and high α₁D binding. If exposures at target tissues are sufficient, α₁D engagement could contribute non-opioid effects (e.g., vascular or smooth muscle modulation); this needs direct functional testing (Ca²⁺ flux or IP₁ assays) at α₁D and human PK to relate in vitro potency to feasible in vivo concentrations [19].

Summary

Binding Affinities
  • α₁D-adrenergic (human, CHO): Kᵢ ≈ 41.7 ± 4.7 nM (radioligand competition with [³H]prazosin).
  • μ-opioid (MOR; human, HEK): Kᵢ ≈ 118 ± 12 nM.
  • κ-opioid (KOR; rat binding, human function): Kᵢ ≈ 1910 ± 50 nM (weak).
  • δ-opioid (DOR): Not quantified; insufficient displacement in screening.
Functional Activity
  • hMOR: Partial agonist (EC₅₀ ≈ 67.2 nM; Emax ≈ 37% vs DAMGO). No β-arrestin-2 recruitment detected (<20%).
  • hKOR / hDOR: No measurable Gi signaling or β-arrestin-2 recruitment at tested ranges.
  • In vivo (mice, i.c.v. dosing): Partial MOR-dependent antinociception (~50% MPE), consistent with partial agonism.
Structure–Activity Context (SAR)

Removal of the C-9 methoxy group (mitragynine → corynantheidine) preserves MOR affinity, markedly reduces KOR affinity, and increases α₁D affinity (~131-fold). Docking studies attribute differences to loss of a methoxy–Thr111 interaction at KOR and altered steric/hydrogen-bonding in subpockets.

Evidence Gaps & Cautions
  • Serotonergic: No validated 5-HT binding/functional data for corynantheidine; serotonergic activity reported only for other kratom indoles (e.g., paynantheine, speciogynine).
  • Adrenergic function: α₁D binding is robust; direct functional α₁D (agonist/antagonist) readouts have not yet been published; antagonist-like behavior remains a hypothesis.
  • Species/assay: hMOR (BRET) vs mMOR ([³⁵S]GTPγS) differ in apparent efficacy; assay type and species context are essential for interpretation.
Practical Implications

Corynantheidine differs from potent MOR agonists: it shows partial MOR agonism, no β-arrestin-2 recruitment, and strong α₁D binding. If in vivo exposures reach relevant concentrations, α₁D engagement may contribute vascular or smooth muscle effects, but functional confirmation and PK studies are still required.

References: [20–25]

Reference Link:

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