URB602

Formula

C₁₉H₂₁NO₂

Molar mass

295.16 g·mol⁻¹

CAS

565460-15-3

PubChem CID

10979337

Origin

A wholly synthetic compound with no natural occurrence. It is produced as an experimental pharmacology reagent and has not been the subject of clinical development.

InChIKey

HHVUFQYJOSFTEH-UHFFFAOYSA-N

Editorial estimate, not clinical.

URB602 played a role out of proportion to its chemical potency, because it arrived at the right moment. In 2005 the physiological role of 2-arachidonoylglycerol remained largely conjectural: this endocannabinoid is by far the most abundant in the brain, but the absence of an inhibitor of the enzyme that degrades it prevented any experimental variation of its concentration. Hohmann and colleagues had this new reagent and used it to settle an old question, that of the mechanism of stress-induced analgesia. It was known that part of that analgesia does not pass through opioids, without knowing what carried it. The work published in Nature establishes the complete chain: stress triggers in the periaqueductal grey matter the rapid formation of 2-arachidonoylglycerol and anandamide, blockade of the CB1 receptor in that region suppresses non-opioid analgesia, and local injection of the inhibitor selectively raises 2-arachidonoylglycerol and enhances the analgesia, in a CB1-dependent manner. The authors conclude by designating monoacylglycerol lipase as a therapeutic target not previously recognised, which it duly became. The compound itself did not follow: its potency lies in the micromolar range and its selectivity is limited, which saw it replaced by finer inhibitors before the end of the decade. The context finally imposes a methodological caveat. The same 2005 work had introduced a second inhibitor, URB754, whose activity subsequently proved entirely attributable to an organomercurial impurity in the commercial lot. That episode reminded the field that the purity of a reagent is part of the demonstration.

An entirely chemical route, described here by class only. The molecule is a biphenyl carbamate: a cyclohexyl group is esterified by a carbamate function whose nitrogen bears a biphenyl substituted at the meta position. It therefore belongs to the carbamate-hinge inhibitors, which inactivate their target enzymes by carbamylating the serine of the active site, a chemistry distinct from that of ureas and fluorophosphonates.

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 an experimental pharmacology reagent and has not been the subject of clinical development.

Status

Unscheduled

1. 1.Hohmann et coll. 2005 : un mécanisme endocannabinoïde de l'analgésie induite par le stressPMID 15973410
2. 2.Makara et coll. 2005 : l'inhibition sélective de l'hydrolyse du 2-AG renforce la signalisation endocannabinoïde dans l'hippocampePMID 16116451