Relative pharmacological potency in mice of optical isomers of Δ1-tetrahydrocannabinol

Jones, Gareth; Pertwee, Roger G.; Gill, E. W.; Patón, W. D. M.; Nilsson, Inger; Widman, M; Agurell, Stig

doi:10.1016/0006-2952(74)90435-3

Cited by 33 publications

(12 citation statements)

References 19 publications

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“…A similar enantiomeric preference applies to blockade of the acrosome reaction (this study) and activation of phospholipase A2 in sperm homogenates (Chang et al, 1991a) as well as to a variety of pharmacological and behavioral effects elicited by ( -)AgTHC and ( +)AgTHC in humans and laboratory mammals (Herkenham et al, 1990). The failure to demonstrate absolute stereoselectivity in these studies may be due to the contamination of (+)AgTHC preparations by (-)AgTHC (Jones et al, 1974;Mechoulam et al, 1991).…”

Section: Discussionsupporting

confidence: 60%

Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction

Chang

Berkery

Schuel

et al. 1993

Molecular Reproduction Devel

101

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Delta-9-tetrahydrocannabinol ((-)delta 9 THC), the primary psychoactive cannabinoid in marihuana, reduces the fertilizing capacity of sea urchin sperm by blocking the acrosome reaction that normally is stimulated by a specific ligand in the egg's jelly coat. The bicyclic synthetic cannabinoid [3H]CP-55,940 has been used as a ligand to demonstrate the presence of a cannabinoid receptor in mammalian brain. We now report that [3H]CP-55,940 binds to live sea urchin (Strongylocentrotus purpuratus) sperm in a concentration, sperm density, and time-dependent manner. Specific binding of [3H]CP-55,940 to sperm, defined as total binding displaced by (-)delta 9THC, was saturable: KD 5.16 +/- 1.02 nM; Hill coefficient 0.98 +/- 0.004. This suggests a single class of receptor sites and the absence of significant cooperative interactions. Sea urchin sperm contain 712 +/- 122 cannabinoid receptors per cell. Binding of [3H]CP-55,940 to sperm was reduced in a dose-dependent manner by increasing concentrations of CP-55,940, (-)delta 9THC, and (+)delta 9THC. The rank order of potency to inhibit binding of [3H]CP-55,940 to sperm and to block the egg jelly stimulated acrosome reaction was: CP-55,940 > (-)delta 9THC > (+)delta 9THC. These findings show that sea urchin sperm contain a stereospecific cannabinoid receptor that may play a role in inhibition of the acrosome reaction. The radioligand binding data obtained with live sea urchin sperm are remarkably similar to those previously published by other investigators using [3H]CP-55,940 on mammalian brain and nonneural tissues. The cannabinoid binding properties of this receptor appear to have been highly conserved during evolution. We postulate that the cannabinoid receptor may modulate cellular responses to stimulation.

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Section: Discussionsupporting

confidence: 60%

Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction

Chang

Berkery

Schuel

et al. 1993

Molecular Reproduction Devel

101

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“…It has been demonstrated that differences in activities do exist for the isomers of THC on mice (Jones et al 1974) and the meail potency ratio was calculated to be 13 and estimated to be at least 20 for the pure compounds. The ( + ) isomer has been shown to be 20-fold less active than the (-) isomer in msnkcys (Edery et al 1971 ) .…”

Section: Discussionmentioning

confidence: 99%

“…The binding of the (+) and ( -) isomers to proteins and blood cells is almost identical ). However, differences in activities have been shown to exist in mice (Jones et al 1974). Recently Lawrencc and Gill (1975) have demonstrated a significarrt difference between the two enantiomers on the mcslccular mobility of the hydrocarbon phase of Iiposomes.…”

Section: Introdl~ctionmentioning

confidence: 96%

Stereospecific presynaptic inhibitory effect of Δ⁹-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig

Roth¹

1978

Can. J. Physiol. Pharmacol.

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delta9-Tetrahydrocannabinol (THC) is very lipid soluble, as are many anesthetic agents. The action of anesthetics is nonspecific; isomers are equieffective. THC is optically active; therefore, the effects of its stereoisomers were studied on the electrically and chemically stimulated longitudinal muscle strip of guinea pig ileum. The results demonstrate that both isomers depress the response to electrical stimulation in a dose-related manner. The maximum effect is gradually reached in approximately 20 min. The (-) isomer is 24.6-fold more active than the (+) isomer (ED50 for (-) THC is 1.25 X 10(-7) M, for (+) THC, 3.08 X 10(-6) M) and the site of action appears to be presynaptic because responses to ACh are not significantly depressed. The depressant effects are relatively nonreversible. Membrane concentrations calculated at the ED50 values for the (-) isomer are of the order of 0.5 mM/kg dry membrane, well within the range for anesthesia. Thus THC may be regarded as a partial anesthetic since some of its actions are similar to those of the classical anesthetics, yet it possesses selective action at the neuronal membrane or tissue level.

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“…1C), which are discussed in more detail below. Studies of the biological effects of THC and its synthetic analogs revealed strict structural selectivity (Hollister, 1974) as well as stereoselectivity (Jones et al, 1974), telltale signs of drugreceptor interactions. Definitive evidence for the existence of specific cannabinoid receptors was followed soon by the demonstration of high-affinity, saturable, stereospecific binding sites for the synthetic cannabinoid agonist [ 3 H]CP-55,940 in mouse brain plasma membranes, which correlated with both the in vitro inhibition of adenylate cyclase and the in vivo analgesic effect of the compound (Devane et al, 1988).…”

Section: A Cannabinoid Receptors and Ligandsmentioning

confidence: 99%

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

2006

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Relative pharmacological potency in mice of optical isomers of Δ1-tetrahydrocannabinol

Cited by 33 publications

References 19 publications

Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction

Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction

Stereospecific presynaptic inhibitory effect of Δ⁹-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

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Relative pharmacological potency in mice of optical isomers of Δ1-tetrahydrocannabinol

Cited by 33 publications

References 19 publications

Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction

Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction

Stereospecific presynaptic inhibitory effect of Δ9-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

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Stereospecific presynaptic inhibitory effect of Δ⁹-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig