Relative pharmacological potency in mice of optical isomers of delta1-tetrahydrocannabinol

G. Jones, Roger Guy Pertwee, E W Gill, W D M Paton, I M Nilsson, M Widman, S Agurell

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Abstract

The tritium-labelled unnatural enantiomorph of ¿1-tetrahydrocannabinol(¿1-THC) was synthesized. The 3H-(+)-¿1-THC had a specific activity of 1.3 Ci/mmole and an optical purity of ca. 97%. The equipotent molar ratio for (+) and (-)-¿1-tetrahydrocannabinols was determined in mice by an established behavioural bioassay. The (+)-¿1-THC was found to be significantly less potent than the laevorotatory isomer, the mean potency ratio being 13 (95 per cent confidence limits: 7 and 24). Brain levels of (+)-¿1-THC and its metabolites were measured in mice 20 min after intravenous injection of 3H-(+)-¿1-THC (2 mg.kg) and were compared with the corresponding levels of (-)-¿1-THC and its metabolites. With the exception of the concentrations of one metabolite, no statistically significant differences were observed between the mean levels of enantiomorphs of the cannabinoids in the brain. In the case of the single metabolite (which was tentatively assigned the structure of 7-hydroxy-¿1-THC) the brain level of the dextrorotatory isomer was 1.8-times higher than that of the laevorotatory isomer, a difference which was statistically significant. On incubation in vitro with an enriched mouse liver homogenate, (+)-¿1-THC was partially metabolized to more polar compounds; the principal metabolite was shown to be (+)-7-hydroxy-¿1-THC. It was concluded that the differences in the psychopharmacological potencies in vivo of the optical isomers of ¿1-THC are determined within the central nervous system and are not due to gross differences in metabolism or body distribution.

Original languageEnglish
Pages (from-to)439-446
Number of pages8
JournalBiochemical Pharmacology
Volume23
Issue number2
DOIs
Publication statusPublished - 15 Jan 1974

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Relative pharmacological potency in mice of optical isomers of delta1-tetrahydrocannabinol. / Jones, G. ; Pertwee, Roger Guy; Gill, E W ; Paton, W D M ; Nilsson, I M ; Widman, M ; Agurell, S .

In: Biochemical Pharmacology, Vol. 23, No. 2, 15.01.1974, p. 439-446.

Research output: Contribution to journalArticle

Jones, G. ; Pertwee, Roger Guy ; Gill, E W ; Paton, W D M ; Nilsson, I M ; Widman, M ; Agurell, S . / Relative pharmacological potency in mice of optical isomers of delta1-tetrahydrocannabinol. In: Biochemical Pharmacology. 1974 ; Vol. 23, No. 2. pp. 439-446.
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abstract = "The tritium-labelled unnatural enantiomorph of ¿1-tetrahydrocannabinol(¿1-THC) was synthesized. The 3H-(+)-¿1-THC had a specific activity of 1.3 Ci/mmole and an optical purity of ca. 97{\%}. The equipotent molar ratio for (+) and (-)-¿1-tetrahydrocannabinols was determined in mice by an established behavioural bioassay. The (+)-¿1-THC was found to be significantly less potent than the laevorotatory isomer, the mean potency ratio being 13 (95 per cent confidence limits: 7 and 24). Brain levels of (+)-¿1-THC and its metabolites were measured in mice 20 min after intravenous injection of 3H-(+)-¿1-THC (2 mg.kg) and were compared with the corresponding levels of (-)-¿1-THC and its metabolites. With the exception of the concentrations of one metabolite, no statistically significant differences were observed between the mean levels of enantiomorphs of the cannabinoids in the brain. In the case of the single metabolite (which was tentatively assigned the structure of 7-hydroxy-¿1-THC) the brain level of the dextrorotatory isomer was 1.8-times higher than that of the laevorotatory isomer, a difference which was statistically significant. On incubation in vitro with an enriched mouse liver homogenate, (+)-¿1-THC was partially metabolized to more polar compounds; the principal metabolite was shown to be (+)-7-hydroxy-¿1-THC. It was concluded that the differences in the psychopharmacological potencies in vivo of the optical isomers of ¿1-THC are determined within the central nervous system and are not due to gross differences in metabolism or body distribution.",
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AU - Widman, M

AU - Agurell, S

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N2 - The tritium-labelled unnatural enantiomorph of ¿1-tetrahydrocannabinol(¿1-THC) was synthesized. The 3H-(+)-¿1-THC had a specific activity of 1.3 Ci/mmole and an optical purity of ca. 97%. The equipotent molar ratio for (+) and (-)-¿1-tetrahydrocannabinols was determined in mice by an established behavioural bioassay. The (+)-¿1-THC was found to be significantly less potent than the laevorotatory isomer, the mean potency ratio being 13 (95 per cent confidence limits: 7 and 24). Brain levels of (+)-¿1-THC and its metabolites were measured in mice 20 min after intravenous injection of 3H-(+)-¿1-THC (2 mg.kg) and were compared with the corresponding levels of (-)-¿1-THC and its metabolites. With the exception of the concentrations of one metabolite, no statistically significant differences were observed between the mean levels of enantiomorphs of the cannabinoids in the brain. In the case of the single metabolite (which was tentatively assigned the structure of 7-hydroxy-¿1-THC) the brain level of the dextrorotatory isomer was 1.8-times higher than that of the laevorotatory isomer, a difference which was statistically significant. On incubation in vitro with an enriched mouse liver homogenate, (+)-¿1-THC was partially metabolized to more polar compounds; the principal metabolite was shown to be (+)-7-hydroxy-¿1-THC. It was concluded that the differences in the psychopharmacological potencies in vivo of the optical isomers of ¿1-THC are determined within the central nervous system and are not due to gross differences in metabolism or body distribution.

AB - The tritium-labelled unnatural enantiomorph of ¿1-tetrahydrocannabinol(¿1-THC) was synthesized. The 3H-(+)-¿1-THC had a specific activity of 1.3 Ci/mmole and an optical purity of ca. 97%. The equipotent molar ratio for (+) and (-)-¿1-tetrahydrocannabinols was determined in mice by an established behavioural bioassay. The (+)-¿1-THC was found to be significantly less potent than the laevorotatory isomer, the mean potency ratio being 13 (95 per cent confidence limits: 7 and 24). Brain levels of (+)-¿1-THC and its metabolites were measured in mice 20 min after intravenous injection of 3H-(+)-¿1-THC (2 mg.kg) and were compared with the corresponding levels of (-)-¿1-THC and its metabolites. With the exception of the concentrations of one metabolite, no statistically significant differences were observed between the mean levels of enantiomorphs of the cannabinoids in the brain. In the case of the single metabolite (which was tentatively assigned the structure of 7-hydroxy-¿1-THC) the brain level of the dextrorotatory isomer was 1.8-times higher than that of the laevorotatory isomer, a difference which was statistically significant. On incubation in vitro with an enriched mouse liver homogenate, (+)-¿1-THC was partially metabolized to more polar compounds; the principal metabolite was shown to be (+)-7-hydroxy-¿1-THC. It was concluded that the differences in the psychopharmacological potencies in vivo of the optical isomers of ¿1-THC are determined within the central nervous system and are not due to gross differences in metabolism or body distribution.

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