8-Hydroxyhexahydrocannabinol

8-Hydroxyhexahydrocannabinols (8-OH-9α-HHC and 8-OH-9β-HHC) are active primary metabolites of hexahydrocannabinol (HHC) in animals and trace phytocannabinoids. The 8-OH-HHCs are produced in notable concentrations following HHC administration in several animal species, including humans. They have drawn research interest for therapeutic use & their role in HHC toxicology and stereoisomeric probes of the cannabinoid drug/receptor interaction.

8-Hydroxyhexahydrocannabinol

Names
Other names 8-OH-HHC
Identifiers
CAS Number	36403-92-6
3D model (JSmol)	Interactive image
ChemSpider	128937963
PubChem CID	102118411
InChI InChI=1S/C21H32O3/c1-5-6-7-8-14-10-18(23)20-15-9-13(2)17(22)12-16(15)21(3,4)24-19(20)11-14/h10-11,13,15-17,22-23H,5-9,12H2,1-4H3/t13-,15+,16+,17+/m0/s1 Key: CIVSDEYXXUHBPV-RKTXRCNFSA-N
SMILES CCCCCC1=CC(=C2[C@@H]3C[C@@H]([C@@H](C[C@H]3C(OC2=C1)(C)C)O)C)O
Properties
Chemical formula	C21H32O3
Molar mass	332.484 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Like Δ9-THC and Δ8-THC, HHC is processed by cytochrome P450 (CYP3A4, CYP2C9 and CYP2C19) to a series of oxygenated derivatives, some of which maintain activity.^[1] While 11-OH-HHC and its downstream products are the major metabolites of HHC metabolism, hydroxylation at C8 plays a varyingly significant role in animal species.^[2][3] Metabolite ratios are also subject to interspecies variation, with one study finding mice hepatocytes preferentially produced 8α-OH-HHC (49/5 α/β) while hamster hematocytes evidenced the opposing selectivity (20/43 α/β).^[2]

While 11-OH-HHC is quickly oxidized to the inactive, water-soluble 11-COOH-HHC, further oxidation of 8-OH instead yields the 8-oxo derivatives, which are then conjugated and excreted.^[4]

Stereoisomerism

Four stereoisomers of 8-OH-HHC arise from C8-hydroxylation of hexahydrocannabinol.

There are four possible 8-OH-HHC metabolites arising from naturally derived HHCs: cis- and trans-8-OH-9α-HHC & cis- and trans-8-OH-9β-HHC. All four have been prepared synthetically to probe stereochemical effects on cannabinoid biological activity.^[5] In in vivo tests on rhesus macaques, Mechoulam and coworkers found the highest activity in the cis-8-OH-9β-HHC stereoisomer.^[6] All four forms are believed to be active.