ECS modulator (research)
UnscheduledNESS-0327NESS 0327
12-chloro-3-(2,4-dichlorophenyl)-N-piperidin-1-yl-3,4-diazatricyclo[8.4.0.02,6]tetradeca-1(10),2(6),4,11,13-pentaene-5-carboxamide
Aliases.NESS 0327 · NESS0327
A CB1 antagonist of femtomolar affinity, the most potent described; a laboratory reagent, never given to humans.
Updated on
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.
Identifiers
- Formula
- C₂₄H₂₃Cl₃N₄O
- Molar mass
- 488.09 g·mol⁻¹
- CAS
- 494844-07-4
- PubChem CID
- 10435654
- Origin
- A wholly synthetic compound with no natural occurrence. It is produced as an experimental pharmacology reagent and has never been the subject of clinical development.
- InChIKey
- NCXBPZJQQSNIRA-UHFFFAOYSA-N
In plain terms
NESS 0327 is the most powerful blocker of the CB1 receptor ever described, with an affinity thousands of times greater than that of rimonabant. It serves as a laboratory tool for switching that receptor off completely. It has never been given to humans.
Receptors and activity
- CB1Ki = 350 ± 5 fM ; pA2 = 12,46 sur canal déférent (Ruiu et coll. 2003)Antagonist
- CB2Ki = 21 ± 0,5 nM ; sélectivité CB1 supérieure à 60 000 foisAntagonist
- Agonist
- Partial agonist
- Antagonist
- Modulator
- Inverse agonist
Hover over a row for the precise value (Ki, EC50…)
Subjective signature
Hover over an axis to read its definition.
- Calm10
- Clarity20
- Sleep10
- Appetite5
- High5
Editorial estimate, not clinical.
Pharmacology
NESS 0327 holds a singular place in cannabinoid pharmacology: it is the highest-affinity antagonist of the CB1 receptor ever published. The value measured by Ruiu and colleagues in 2003, an inhibition constant of 350 femtomolar, corresponds to an affinity roughly five thousand times greater than that of rimonabant assessed under the same conditions. Its selectivity follows the same pattern: more than 60 000 times in favour of CB1 over CB2, where rimonabant tops out at 285 times. The gain comes from a design choice that is simple in principle: closing the pyrazole skeleton of rimonabant into a tricyclic system, which removes the freedom of rotation between the rings and locks the molecule into the exact geometry the receptor recognises. The compound does not activate the receptor by itself in G protein coupling assays, and it efficiently displaces agonists, which led it to be regarded as an antagonist rather than an inverse agonist. That extreme affinity makes it a valuable tool for establishing that a given effect really does pass through CB1, since very low concentrations suffice to saturate the receptor. It also makes it a poor drug candidate: binding that durable leaves little room for dose adjustment, and the whole class of CB1 antagonists remains marked by the withdrawal of rimonabant from the European market in 2008 for adverse psychiatric effects. The compound has remained a laboratory reagent.
Origin (research tool)
An entirely chemical route, described here by class only. The molecule belongs to the tricyclic pyrazoles: the pyrazole core of rimonabant is fused to a benzocycloheptane ring, which locks the relative geometry of the substituents instead of leaving it free. It retains the two motifs characteristic of the series, a dichlorophenyl on the nitrogen and a piperidine carboxamide, and adds a chlorine on the tricyclic portion.
Legal framework
France
A substance not listed by name in Annex IV of the arrêté of 22 February 1990 setting out the list of narcotics. Its tricyclic pyrazole antagonist structure falls under none of the twelve families of synthetic cannabinoids added by the arrêté of 31 March 2017, which target agonists with an indole, indazole, pyrrole, indene or cyclohexylphenol skeleton. The compound holds the status of a laboratory reagent.
European Union
No harmonised control measure at Union level and no listing under the international conventions of 1961 and 1971. The compound was not developed clinically and has never been reported on the new psychoactive substances market.
Sources: EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA. Our method.
Structural classification
- Class
- ECS modulator (research)
- Origin
- A wholly synthetic compound with no natural occurrence. It is produced as an experimental pharmacology reagent and has never been the subject of clinical development.
- Status
- Unscheduled
References
Structured data
- InChIKey
- NCXBPZJQQSNIRA-UHFFFAOYSA-N
- SMILES
- C1CCN(CC1)NC(=O)C2=NN(C3=C2CCCC4=C3C=CC(=C4)Cl)C5=C(C=C(C=C5)Cl)Cl
- Formula
- C24H23Cl3N4O
- Molar mass
- 488.09 g·mol⁻¹
- CAS
- 494844-07-4
- PubChem CID
- 10435654
LLM ingestion format: a structured superset of the entry (identifiers, binding, versioned legal status). Full corpus.