O-2050

Formula

C₂₃H₃₁NO₄S

Molar mass

417.20 g·mol⁻¹

CAS

-

PubChem CID

16102146

Origin

A wholly synthetic compound with no natural occurrence. It is produced as a pharmacology reagent and has never been the subject of clinical development.

InChIKey

DJTGGIYZQHHLGJ-RTBURBONSA-N

Editorial estimate, not clinical.

O-2050 illustrates a recurring problem in cannabinoid pharmacology: the difficulty of obtaining a genuinely neutral antagonist of the CB1 receptor. Rimonabant, the first reference antagonist, behaves at high concentration as an inverse agonist, meaning that it reduces the constitutive activity of the receptor in the absence of any agonist. That property blurs the interpretation of experiments and complicates the reading of adverse effects. Chemists therefore looked for molecules that simply occupy the site without closing it. O-2050, a sulfonamide analogue of Δ8-THC bearing an acetylenic chain, was one of the most widely used candidates for that purpose. Wiley and colleagues carried out its systematic evaluation in 2011 and the result is clear in both directions. In vitro the compound does behave as an antagonist: it displaces agonists and blocks their signal with no effect of its own. In vivo it does the opposite of what an antagonist is expected to do. It does not block agonists, even delivered directly into the brain, and it fully substitutes for Δ9-THC in mice trained to recognise that molecule, which is the behavioural signature of an agonist. The measurement of cyclic AMP signalling settles the matter: efficacy reaches about half that of a full agonist, the profile of a partial agonist. The authors conclude that the compound cannot be classified as a neutral antagonist. The consequence goes beyond the molecule itself: earlier work that had interpreted a reduction in food intake under O-2050 as proof of CB1 blockade rests on a false premise.

An entirely chemical route, described here by class only. The skeleton is that of a classical cannabinoid dibenzopyran, broadly identical to that of Δ8-THC, from which it differs by the replacement of the pentyl chain with a hexynyl chain capped by a methanesulfonamide group. It is this side-chain substitution, and not a modification of the tricyclic core, that was meant to produce the change in activity sought.

Sources: EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA. Our method.

Class

ECS modulator (research)

Origin

A wholly synthetic compound with no natural occurrence. It is produced as a pharmacology reagent and has never been the subject of clinical development.

Status

Unscheduled

1. 1.Wiley et coll. 2011 : analyse structurale et pharmacologique de l'O-2050, prétendu antagoniste neutre du CB1PMID 21114999