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Research tools

ORG27569

Negative allosteric modulator of CB1, a laboratory tool whose reference status is debated.

Unscheduled
Level of detail

Harm-reduction warning

No characterised human dose: animal / in vitro data only. Effect profile, safety margin and acute toxicity are not documented in human clinical practice. Extremely potent compound: severe effects, seizures and deaths reported in the literature.

C₂₄H₂₈ClN₃O

CAS 868273-06-7

Family
ECS pharmacological toolAllosteric modulator
Molar mass
409.90 g/mol

Updated on

In plain terms

Org 27569 is a laboratory molecule, made by synthesis and unrelated to hemp. It was used to show that the CB1 receptor has a second attachment point, distinct from the one where THC and other cannabinoids bind. It is used only as a research reagent; the data cited come from cells and animals.

Receptors and activity

Target network

CB1 (allosteric site)Negative allosteric modulatorKd = 217 nMequilibrium dissociation constant KB (95% confidence interval 170.3 to 277.2 nM) of ORG27569 (compound 1); binding cooperativity α = 6.95 with [3H]CP 55,940; membranes of HEK293 cells expressing CB1
  • Blocks or inhibits

The lower the cited value, the closer the target sits to ORG27569: one ring per factor of 100. A target with no measured value stays on the edge.

Where these targets live

Where each target has been found in humans, according to the cited studies. The map shows the target, not an effect of ORG27569.

Brain, side view
Body, front view
Blood

CB1CB1 found in 7 regions of the body

  1. Basal gangliadenseMost dense in basal ganglia outflow nuclei1
  2. CerebellumdenseVery dense in the cerebellum1
  3. HippocampusdenseVery high concentrations in the hippocampus2
  4. AmygdaladenseHigh concentrations in the amygdala2
  5. CortexpresentPresent throughout the neocortex2
  6. Adipose tissuepresentExpressed in adipose tissue3
  7. GutpresentColonic epithelium, smooth muscle and plexus4

Map sources

  1. Herkenham M et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A, 1990 (new tab)
  2. Glass M et al. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience, 1997 (new tab)
  3. Engeli S et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes, 2005 (new tab)
  4. Wright K et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology, 2005 (new tab)

Cited values

  1. CB1 (allosteric site)Negative allosteric modulatorKd = 217 nM44 out of 100

    Mahmoud et al., J Med Chem 2013 (new tab) · equilibrium dissociation constant KB (95% confidence interval 170.3 to 277.2 nM) of ORG27569 (compound 1); binding cooperativity α = 6.95 with [3H]CP 55,940; membranes of HEK293 cells expressing CB1

  2. CB1 (phosphorylation d'ERK1/2 induite par le CP 55,940)Negative allosteric modulatorIC50 = 165 nM · human46 out of 100

    Gamage et al., Cannabis Cannabinoid Res 2016 (new tab) · HEK293 cells expressing human CB1; complete block of CP 55,940 (pIC50 6.78); incomplete block of THC (pIC50 6.38) and 2-AG (pIC50 6.26)

Bar length follows the measured value (Ki, Kd, EC50 or IC50), on one scale shared by every entry, from 100 µM to 0.1 nM. A target with no cited value has no bar.

Pharmacology

Org 27569 is an indole-2-carboxamide with no structural kinship with cannabinoids. Described in 2005 (Price et al.), it provided evidence that the CB1 receptor has an allosteric site, localised in 2019 outside the orthosteric pocket, in the inner leaflet of the membrane (Shao et al. 2019). Its profile is paradoxical: it increases the binding of orthosteric agonists (KB of 217.3 nM, α of 6.95; Mahmoud et al. 2013) while antagonising Gi signalling, cAMP and β-arrestin recruitment, with strong agonist dependence (Baillie et al. 2013); Green et al. (2024) attribute to it a kinetic lag in cAMP effect linked to signal amplification and a comparable interaction with CP 55,940 and WIN 55,212-2. In vivo effects are less clear. In mice, it reduced food intake independently of CB1 and changed neither the antinociception, catalepsy nor hypothermia induced by CB1 agonists, nor drug discrimination; the authors question its usefulness as a reference modulator (Gamage et al. 2014). In rats, 1.0 to 5.6 mg/kg intraperitoneally attenuated in a dose-related manner the reinstatement of cocaine- and methamphetamine-seeking induced by cues or a priming injection, as SR141716A did (Jing et al. 2014). In oxycodone withdrawal in mice, the fall in jumping at 10 and 30 mg/kg was confounded by reduced locomotion, and the 3 mg/kg dose did not change the withdrawal behaviours measured (Scicluna et al. 2024). All these data are preclinical.

Key sources.

History

Source
A synthetic molecule of the indole-2-carboxamide class, absent from hemp and from any living organism. A laboratory reagent, a tool of experimental pharmacology.

Origin

Research tool

No biosynthetic pathway: a synthetic molecule of the indole-2-carboxamide class, with no cannabinoid precursor.

Classification

Family, origin and source verification

Family

ECS pharmacological tool › Allosteric modulator

Verification

Classification, sources and binding values checked on 20 October 2026; text read against its sources and Wikipedia.

Wikipedia (English)

Org 27569 (new tab)

Article paired by the molecule's structure (InChIKey), revision read on 19 October 2026. Read as a second opinion, never cited as a source.

References

  1. Price MR et al., Allosteric modulation of the cannabinoid CB1 receptor, Mol Pharmacol 2005 (new tab)PMID 16113085
  2. Ahn KH, Mahmoud MM, Kendall DA, Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation, J Biol Chem 2012 (new tab)PMID 22343625
  3. Baillie GL et al., CB1 receptor allosteric modulators display both agonist and signaling pathway specificity, Mol Pharmacol 2013 (new tab)PMID 23160940
  4. Mahmoud MM et al., Structure-activity relationship study of indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1), J Med Chem 2013 (new tab)PMID 24053617
  5. Gamage TF et al., In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569, Behav Pharmacol 2014 (new tab)PMID 24603340
  6. Jing L, Qiu Y, Zhang Y, Li JX, Effects of the cannabinoid CB1 receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats, Drug Alcohol Depend 2014 (new tab)PMID 25169627
  7. Gamage TF, Anderson JC, Abood ME, CB1 allosteric modulator Org27569 is an antagonist/inverse agonist of ERK1/2 signaling, Cannabis Cannabinoid Res 2016 (new tab)PMID 28660254
  8. Shao Z et al., Structure of an allosteric modulator bound to the CB1 cannabinoid receptor, Nat Chem Biol 2019 (new tab)PMID 31659318
  9. Green HM et al., Insight into the mechanism of action of ORG27569 at the cannabinoid type one receptor utilising a unified mathematical model, Naunyn Schmiedebergs Arch Pharmacol 2024 (new tab)PMID 38227196
  10. Scicluna RL et al., Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice, Psychopharmacology 2024 (new tab)PMID 38676755
  11. RCSB Protein Data Bank, entry 6KQI (structure of CB1 with ORG27569 and CP55940, Shao et al. 2019) (new tab)
  12. ANSM, Consolidated list of substances classified as narcotics, updated 16 February 2026, annex IV (new tab)
  13. PubChem, compound CID 44828492 (Org 27569) (new tab)

Identifiers

Names

IUPAC name
5-chloro-3-ethyl-N-[2-(4-piperidin-1-ylphenyl)ethyl]-1H-indole-2-carboxamide
Other names
Org 27569

Identifiers

Formula
C₂₄H₂₈ClN₃O
CAS
868273-06-7
PubChem CID
44828492(new tab)
InChIKey
AHFZDNYNXFMRFQ-UHFFFAOYSA-N
SMILES
CCC1=C(NC2=C1C=C(C=C2)Cl)C(=O)NCCC3=CC=C(C=C3)N4CCCCC4

Machine-readable entry (JSON)

LLM ingestion format: a structured superset of the entry (identifiers, binding, versioned legal status). Full corpus.