Abstract

Cannabidiol (CBD), a nonpsychoactive cannabinoid, was found to be converted to 9α-hydroxyhexahydrocannabinol (9α-OH-HHC) and 8-hydroxy-iso-hexahydrocannabinol (8-OH-iso-HHC) together with Δ⁹-tetrahydrocannabinol (Δ⁹-THC), a psychoactive cannabinoid, and cannabinol in artificial gastric juice. These cannabinoids were identified by gas chromatography-mass spectrometry (GC-MS) by comparison with the spectral data of the authentic compounds. Pharmacological effects of 9α-OH-HHC and 8-OH-iso-HHC in mice were examined using catalepsy, hypothermia, pentobarbital-induced sleep prolongation, and antinociception against acetic acid-induced writhing as indices. The ED₅₀ values (effective dose producing a 50% reduction of control; mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC for the cataleptogenic effect were 8.0 and 30.4, respectively. 8-OH-iso-HHC (10 mg/kg, i.v.) produced a significant hypothermia from 15 to 90 min after administration, although 9α-OH-HHC failed to induce such an effect at the same dose. However, both HHCs (10 mg/kg, i.v.) significantly prolonged pentobarbital-induced sleeping time by 1.8 to 8.0 times as compared with the control solution with 1% Tween 80-saline. The ED₅₀ values (mg/kg, i.v.) of 9α-OH-HHC and 8-OH-iso-HHC for the antinociceptive effect were 14.1 and 39.4, respectively. The present study demonstrated that CBD can be converted to Δ⁹-THC and its related cannabinoids, 9α-OH-HHC and 8-OH-iso-HHC, in artificial gastric juice, and that these HHCs show Δ⁹-THC-like effects in mice, although their pharmacological effects were less potent than those of Δ⁹-THC.

Keywords

Cannabidiol Δ⁹-Tetrahydrocannabinol 9α-Hydroxyhexahydrocannabinol 8-Hydroxy-iso-hexahydrocannabinol Acid-catalyzed cyclization Antinociceptive effect

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References

1.

Mechoulam R, Shani A, Edery H, Grunfeld Y (1970) The chemical basis of hashish activity. Science 169:383–393CrossRefGoogle Scholar
2.

Hollister LE (1973) Cannabidiol and cannabinol in man. Experientia 29:825–826PubMedCrossRefGoogle Scholar
3.

Hollister LE (1974) Structure-activity relationships in man of cannabis constituents and homologs and metabolites for Δ⁹-tetrahydrocannabinol. Pharmacology 11:3–11PubMedCrossRefGoogle Scholar
4.

Adams R, Pease DC, Cain CK, Clark JH (1940) Structure of cannabidiol. VI. Isomerization of cannabidiol to tetrahydrocannabinol, a physiologically active product. Conversion of cannabidiol to cannabinol. J Am Chem Soc 62:2402–2405CrossRefGoogle Scholar
5.

Adams R, Cain CK, McPhee WD, Wearn RB (1941) Structure of cannabidiol. XII. Isomerization to tetrahydrocannabinols. J Am Chem Soc 63:2209–2213CrossRefGoogle Scholar
6.

Gaoni Y, Mechoulam R (1966) Hashish-VII, the isomerization of cannabidiol to tetrahydrocannabinols. Tetrahedron 22:1481–1488CrossRefGoogle Scholar
7.

Gaoni Y, Mechoulam R (1968) The iso-tetrahydrocannabinols. Israel J Chem 6:679–690Google Scholar
8.

Quarles W, Ellman G, Jones R (1973) Toxicology of marihuana: conditions for conversion of cannabidiol to THC upon smoking. Clin Toxicol 6:211–216PubMedCrossRefGoogle Scholar
9.

Nagai K, Watanabe K, Narimatsu S, Gohda H, Matsunaga T, Yamamoto I, Yoshimura H (1993) In vitro metabolic formation of a new metabolite, 6β-hydroxymethyl-Δ⁹-tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice. Biol Pharm Bull 16:1008–1013PubMedGoogle Scholar
10.

Aramaki H, Tomiyasu N, Yoshimura H, Tsukamoto H (1968) Forensic chemical study on marihuana. I. A detection method of the principal constituents by thin-layer and gas chromatographies. Chem Pharm Bull 16:822–826PubMedGoogle Scholar
11.

Petrzilka T, Demuth M (1974) Synthese von (−)-11-hydroxy-Δ⁸-6a,10a-trans-tetrahydrocannabinol. Helv Chim Acta 57:121–150PubMedCrossRefGoogle Scholar
12.

Yoshimura H, Watanabe K, Oguri K, Fujiwara M, Ueki S (1978) Synthesis and pharmacological activity of a phosphate ester of Δ⁸-tetrahydrocannabinol. J Med Chem 21:1079–1081PubMedCrossRefGoogle Scholar
13.

Watanabe K, Kijima T, Narimatsu S, Nishikami J, Yamamoto I, Yoshimura H (1990) Comparison of pharmacological effects of tetrahydrocannabinols and their 11-hydroxymetabolites in mice. Chem Pharm Bull 38:2317–2319PubMedGoogle Scholar
14.

Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113PubMedGoogle Scholar
15.

Wilson RS, May EL, Martin BR, Dewey WL (1976) 9-Nor-9-hydroxyhexahydrocannabinols. Synthesis, some behavioral and analgesic properties, and comparison with the tetrahydrocannabinols. J Med Chem 19:1165–1167PubMedCrossRefGoogle Scholar
16.

Skinner WA, Rackur G, Uyeno E (1979) Structure-activity studies on tetrahydro-and hexahydrocannabinol derivatives. J Pharm Sci 68:330–332PubMedCrossRefGoogle Scholar
17.

Ganz AJ, Waser PG (1980) Prufung der pharmakologischen wirkung einiger synthetischer Cannabinoide an der Maus. Arzneim-Forsch 30:471–477Google Scholar
18.

Narimatsu S, Yamamoto I, Watanabe K, Yoshimura H (1983) 9α, 10α-Epoxyhexahydrocannabinol formation from Δ⁹-tetrahydrocannabinol by liver microsomes of phenobarbital-treated mice and its pharmacological activities in mice. J Pharmacobio-Dyn 6:558–564PubMedGoogle Scholar
19.

Holtzman D, Lovell RA, Jaffe JH, Freedman DX (1969) l-Δ⁹-Tetrahydrocannabinol: neurochemical and behavioral effects in the mouse. Science 163:1464–1467PubMedCrossRefGoogle Scholar
20.

Lomax P (1971) Acute tolerance to the hypothermic effect of marihuana in the rat. Res Commun Chem Path Pharmacol 2:159–167Google Scholar
21.

Haavik CO, Hardman HF (1973) Evaluation of the hypothermic action of tetrahydrocannabinols in mice and squirrel monkeys. J Pharmacol Exp Ther 187:568–574PubMedGoogle Scholar
22.

Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96:5780–5785PubMedCrossRefGoogle Scholar
23.

Fernandes M, Schabarek A, Coper H, Hill R (1974) Modification of Δ⁹-THC actions by cannabinol and cannabidiol in the rat. Psychopharmacology 38:329–338CrossRefGoogle Scholar
24.

Turkanis SA, Cely W, Olsen DM, Karler R (1974) Anticonvulsant properties of cannabidiol. Res Commun Chem Path Pharmacol 8:231–246Google Scholar
25.

Chiu P, Karler R, Craven C, Olsen DM, Turkanis SA (1975) The influence of Δ⁹-tetrahydrocannabinol, cannabinol and cannabidiol on tissue oxygen consumption. Res Commun Chem Path Pharmacol 12:267–286Google Scholar
26.

Bloom AS, Johnson KM, Dewey WL (1978) The effects of cannabinoids on body temperature and brain catecholamine synthesis. Res Commun Chem Path Pharmacol 20:51–57Google Scholar
27.

Yamamoto I, Watanabe K, Kuzuoka K, Narimatsu S, Yoshimura H (1987) The pharmacological activity of cannabinol and its major metabolite, 11-hydroxycannabinol. Chem Pharm Bull 35:2144–2147PubMedGoogle Scholar
28.

Paton WD, Pertwee RG (1972) Effects of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br J Pharmacol 44:250–261PubMedGoogle Scholar
29.

Coldwell BB, Bailey K, Paul CJ, Anderson G (1974) Interaction of cannabinoids with pentobarbital in rats. Toxicol Appl Pharmacol 29:59–69PubMedCrossRefGoogle Scholar
30.

Siemens AJ, Kalant H, Khana M, Marshman J, Ho G (1974) Effect of cannabis on pentobarbital-induced sleeping time and pentobarbital metabolism in the rat. Biochem Pharmacol 23:477–488PubMedCrossRefGoogle Scholar
31.

Borys HK, Ingall GB, Karler R (1979) Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol. Br J Pharmacol 67:93–101PubMedGoogle Scholar
32.

Watanabe K, Arai M, Narimatsu S, Yamamoto I, Yoshimura H (1987) Self-catalyzed inactivation of cytochrome P-450 during microsomal metabolism of cannabidiol. Biochem Pharmacol 36:3371–3377PubMedCrossRefGoogle Scholar
33.

Buxbaum DM (1972) Analgesic activity of Δ⁹-tetrahydrocannabinol in the rat and mouse. Psychopharmacologia 25:275–280PubMedCrossRefGoogle Scholar
34.

Sofia RD, Nalepa SD, Harakal JJ, Vassar HB (1973) Antiedema and analgesic properties of Δ⁹-tetrahydrocannabinol (THC). J Pharmacol Exp Ther 186:646–655PubMedGoogle Scholar

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Conversion of cannabidiol to Δ9-tetrahydrocannabinol and related cannabinoids in artificial gastric juice, and their pharmacological effects in mice

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