4-O-methylhonokiol

Formula

C₁₉H₂₀O₂

Molar mass

280.15 g·mol⁻¹

CAS

68592-15-4

PubChem CID

155160

Origin

A natural product of plant origin, from the genus Magnolia, where it accompanies honokiol and magnolol, of which it is the methylated derivative. It does not come from cannabis: its connection to the endocannabinoid system rests on its affinity for the CB2 receptor and on its action on the metabolism of 2-arachidonoylglycerol.

InChIKey

OQFHJKZVOALSPV-UHFFFAOYSA-N

Editorial estimate, not clinical.

4-O-methylhonokiol is one of the clearest examples of a cannabinoid ligand from a plant unrelated to cannabis. Magnolias produce a family of biphenyl neolignans, honokiol and magnolol foremost among them, long used in the pharmacopoeias of East Asia. Schuehly and colleagues showed in 2011 that the methylated derivative of one of them binds to the CB2 receptor with an inhibition constant below 50 nanomolar and a distinct selectivity, which is remarkable for a chemical scaffold bearing no resemblance to the cannabinoids. Its functional behaviour is more remarkable still. The molecule produces at the same time two ordinarily opposed responses: inverse agonism on the cyclic AMP pathway coupled to the Gi protein, and a strong rise in intracellular calcium that depends on the CB2 receptor. The authors describe that dissociation as a novel type of functional heterogeneity and exploit it to settle a precise question: it is indeed CB2-dependent cyclic AMP formation, and not calcium, that governs the formation of osteoclasts, the cells that resorb bone. Chicca and colleagues added in 2015 a second route of action, independent of the first. Cyclooxygenase 2, known for making prostaglandins, also oxidises 2-arachidonoylglycerol and thereby contributes to its disappearance. The molecule selectively inhibits that second function without touching the first, which raises brain concentrations of that endocannabinoid in mice in a dose-dependent manner. That substrate-selective inhibition mechanism is a finer route than the complete blockade of an enzyme, since it leaves the main physiological function of the target intact.

A plant phenylpropanoid biosynthetic route leading to the neolignan skeleton by oxidative coupling of two units derived from cinnamic acid. The result is a biphenyl in which each ring bears an allyl chain, one of the two bearing a free hydroxyl and the other a methoxy group. That biphenyl architecture bears no kinship with the terpenophenolic skeleton of the cannabis cannabinoids, which is what makes its affinity for the CB2 receptor interesting.

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

Class

ECS modulator (research)

Origin

A natural product of plant origin, from the genus Magnolia, where it accompanies honokiol and magnolol, of which it is the methylated derivative. It does not come from cannabis: its connection to the endocannabinoid system rests on its affinity for the CB2 receptor and on its action on the metabolism of 2-arachidonoylglycerol.

Status

Unscheduled

1. 1.Schuehly et coll. 2011 : mécanismes d'inhibition de l'ostéoclastogenèse par une classe nouvelle d'agonistes inverses biphényliques du récepteur CB2PMID 21867920
2. 2.Chicca et coll. 2015 : le 4'-O-méthylhonokiol élève le 2-arachidonoylglycérol cérébral chez la souris par inhibition sélective de son oxygénation par la COX-2PMID 25962384
3. 3.Lin et coll. 2025 : imagerie par tomographie par émission de positons du ligand du récepteur CB2 4-O-[11C]méthylhonokiol dans un modèle de gliome chez le ratPMID 40773909