GAT100

Formula

C₂₅H₂₈N₄OS

Molar mass

432.60 g·mol⁻¹

CAS

-

PubChem CID

117923261

Origin

A wholly synthetic compound with no natural occurrence. It is produced as a pharmacological probe for mapping the allosteric site of the CB1 receptor and has no clinical use.

InChIKey

OZEQTGDZTPJNAR-UHFFFAOYSA-N

Editorial estimate, not clinical.

GAT100 is a covalent probe of the allosteric site of the CB1 receptor, designed to solve a precise methodological problem. The two historical negative allosteric modulators of that receptor, Org27569 and PSNCBAM-1, display an inverse agonism that blurs the interpretation of their effects: it is not always possible to separate what belongs to allosteric modulation proper from what belongs to a direct action on the constitutive activity of the receptor. Laprairie and colleagues screened a library of electrophilic and photoactivatable analogues of those two compounds and retained this one, bearing an isothiocyanate, as lead. The functional profile established across five downstream signalling pathways, beta-arrestin 1 recruitment, phosphorylation of phospholipase C beta 3 and of the ERK1/2 kinases, cyclic AMP accumulation and receptor internalisation, shows that it attenuates the response to the synthetic agonist CP55,940 as well as that of the two endocannabinoids, in three cellular systems two of which express the receptor endogenously. It proved more potent and more efficacious than its two models, and above all devoid of their inverse agonism in the labelled GTPγS assay. Its covalent nature, which fixes it durably to the receptor, makes it a marker usable for mapping the allosteric site itself, and docking simulations designate the cysteine 7.38(382) residue as anchor point. The practical stake is therapeutic in the longer run: modulating CB1 activity without activating or blocking it head-on would offer a route of access to that target without the adverse effects that caused orthosteric agonists and antagonists to fail.

An entirely chemical route, described here by class only. The molecule derives from the indole-2-carboxamide skeleton of Org27569, whose ethyl chain linked to a piperidine-substituted phenyl it retains. The decisive modification is the introduction of an isothiocyanate function on the indole core, an electrophilic group able to form a covalent bond with a residue of the receptor.

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 pharmacological probe for mapping the allosteric site of the CB1 receptor and has no clinical use.

Status

Unscheduled

1. 1.Laprairie et coll. 2016 : cartographie du site allostérique du CB1, déterminant moléculaire et profil de signalisation du GAT100PMID 27046127
2. 2.Kulkarni et coll. 2016 : sondes covalentes électrophiles et de photomarquage du site allostérique du récepteur CB1PMID 26529344