ParacetamolParacetamol (acetaminophen)

Formula

C₈H₉NO₂

Molar mass

151.06 g·mol⁻¹

CAS

103-90-2

PubChem CID

1983

Origin

A synthetic molecule, produced industrially as a medicinal active substance. It is not of cannabis origin and does not belong to the phytocannabinoids: its inclusion here rests on the fact that part of its analgesic action passes through a metabolite that acts on the endocannabinoid system and on the TRPV1 receptor.

InChIKey

RZVAJINKPMORJF-UHFFFAOYSA-N

Editorial estimate, not clinical.

Paracetamol occupies an unexpected place in an encyclopaedia of cannabinoids, and it occupies it legitimately. In use for more than a century, prescribed and consumed more than any other analgesic, it long had the awkward distinction of being a medicine whose action nobody could really explain: its peripheral anti-inflammatory effects are weak, which sets it apart from the non-steroidal anti-inflammatories, and inhibition of cyclooxygenases does not satisfactorily account for it. The answer found in 2005 by Högestätt and colleagues at the University of Lund shifts the question from the compound to its metabolite. Paracetamol is deacetylated to 4-aminophenol, and that molecule is taken up in the nervous system by fatty acid amide hydrolase, the enzyme that ordinarily cleaves anandamide. Used in reverse, it builds: it conjugates 4-aminophenol to arachidonic acid to produce AM404, a molecule whose structure is that of an endocannabinoid and which potently activates the TRPV1 receptor while hindering anandamide reuptake. Barrière and colleagues closed the demonstration in 2013 with the tools of genetics: neither the metabolite nor the antinociceptive effect appears in mice lacking the enzyme, and the effect disappears in mice lacking the TRPV1 receptor. In rats, antinociception is furthermore suppressed by blockade of the CB1 receptor and by destruction of the descending serotonergic pathways, which places the mechanism within a pain control circuit and not in a local action. That history explains why paracetamol figures in inventories of endocannabinoid system modulators: it is not a cannabinoid, it is an ordinary medicine from which the body manufactures one.

An entirely chemical route, described here by class only. The molecule is a very simple aromatic amide: a phenol ring bears an acetamide function at the para position. The remarkable point is not its industrial manufacture but its transformation in the body: deacetylation releases 4-aminophenol, which fatty acid amide hydrolase then conjugates to arachidonic acid to form AM404, a molecule whose structure is that of an endocannabinoid of the N-acylethanolamine family.

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

Class

ECS modulator (research)

Origin

A synthetic molecule, produced industrially as a medicinal active substance. It is not of cannabis origin and does not belong to the phytocannabinoids: its inclusion here rests on the fact that part of its analgesic action passes through a metabolite that acts on the endocannabinoid system and on the TRPV1 receptor.

Status

Unscheduled

1. 1.Högestätt et coll. 2005 : conversion de l'acétaminophène en N-acylphénolamine bioactive AM404 par conjugaison à l'acide arachidonique dépendante de la FAAH dans le système nerveuxPMID 15987694
2. 2.Barrière et coll. 2013 : génération dépendante de la FAAH de métabolites antinociceptifs agissant sur le TRPV1 dans le cerveauPMID 23940628