MAFPMethoxy arachidonyl fluorophosphonate

Formula

C₂₁H₃₆FO₂P

Molar mass

370.50 g·mol⁻¹

CAS

-

PubChem CID

10429254

Origin

A wholly synthetic compound with no natural occurrence. It is produced as a biochemical research reagent and has no human or veterinary use.

InChIKey

KWKZCGMJGHHOKJ-ZKWNWVNESA-N

Editorial estimate, not clinical.

Methoxy arachidonyl fluorophosphonate is an organophosphorus compound designed on a simple principle: carrying a reactive head on a motif that the target enzyme recognises as its substrate. The arachidonic chain ensures recognition by fatty acid amide hydrolase, and the fluorophosphonate phosphorylates the catalytic serine residue, which inactivates the enzyme irreversibly. Deutsch and colleagues established in 1997 that this combination made it about 800 times more potent than the reversible inhibitors then available on rat brain homogenates, and about a thousand times on intact cells, with a selectivity of three to four orders of magnitude with respect to chymotrypsin and trypsin. It was thus the first tool allowing the degradation of anandamide to be durably suppressed, a step without which the physiological role of that endocannabinoid remained difficult to establish. The same publication nevertheless flagged the decisive limitation of the compound: it also binds the CB1 receptor, which it occupies irreversibly with a median inhibitory concentration of 20 nanomolar, a value better than that of anandamide itself. A tool meant to measure the effect of an elevation of anandamide therefore acts simultaneously on the target of that same anandamide, which makes the interpretation of any result obtained with it delicate. The subsequent literature confirmed that arachidonic fluorophosphonates in fact inhibit a broad set of serine hydrolases, including the cytosolic phospholipases A2. The compound remains in use as a broad biochemical reagent, but it has been superseded as a selective tool by the inhibitors of the following generation, such as URB597.

An entirely chemical route, described here by class only. The molecule combines the arachidonic chain of twenty carbons and four double bonds, recognised by the enzymes that handle endocannabinoids, with a methylated fluorophosphonate group that constitutes the reactive head. That architecture illustrates a classical strategy of inhibitor design: grafting an electrophile onto the recognition motif of the natural substrate.

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 biochemical research reagent and has no human or veterinary use.

Status

Unscheduled

1. 1.Deutsch et coll. 1997 : le MAFP, inhibiteur irréversible puissant de l'amidase de l'anandamidePMID 9065728