| Published Scientific Papers on Thujone |
Molar Volume Relationships and the Specific Inhibition of a Synaptosomal Enzyme
by Psychoactive Cannabinoids
By Jeffrey H. Greenberg, Alan Mellors and John C. McGowan
Published in Journal of Medicinal Chemistry, 1978, Vol. 21, No. 12
by Psychoactive Cannabinoids
By Jeffrey H. Greenberg, Alan Mellors and John C. McGowan
Published in Journal of Medicinal Chemistry, 1978, Vol. 21, No. 12
Abstract
The ability of a number of lipophilic compounds to inhibit the mouse-brain synaptosomal enzyme acyl coenzyme
Alysophosphatidylcholine acyltransferase has been measured in vitro. Psychoactive cannabinoids inhibit the enzyme at concentrations
much lower than is predicted from their capacity to act as lipid-soluble anesthetics. Nonpsychoactive cannabinoids do not show
specific inhibition. Molar volume relationships are used to show that, while all lipid-soluble molecules exert some inhibitory effect in
proportion to their ability to dissolve in biological membranes, psychoactive cannabinoids have an inhibitory effect greatly in excess of
their anesthetic potency. The isoprenoid convulsant thujone has been suggested to have psychoactivity similar to cannabinoids but
does not mimic the cannabinoids in inhibiting the synaptosomal enzyme. Molar volumes and specific interactions are used in
structure-activity correlations which yield information on the relative concentrations of hiophase in drug-responsive systems and the
specificity of membrane-active drugs.
Introduction
The psychoactive constituents of marihuana are the cannabinoids, the principal component being (-)-trans-A9-tetrahydrocannabinol
(A9-THC). A variety of other natural and synthetic cannabinoids of varying psychoactive potencies which depend on side-chain
substitutions and ring modifications have been described. One explanation of cannabinoid psychoactivity that has gained wide
acceptance is the "partial anesthetic" hypothesis and is based on the ability of cannabinoids to cause membrane perturbations similar
to those seen for many lipid-soluble anesthetics. We report here the inhibition of a membrane-bound enzyme in synaptosomes by
psychoactive
cannabinoids at concentrations well below those required to produce nonspecific anesthetic effects or molar volume dependent
membrane perturbations.
The high lipid solubility of the cannabinoids would suggest that their action be at least partly mediated at the level of cell membranes. A
variety of nonspecific effects on cannabinoids on cell membrane processes have been described, including inhibition of lymphocytic
transformation,lysosomal lysis, mitochondrial disruption, and the uptake of putative neurotransmitters by mouse-brain synaptosomes.
Recently some membrane processes have been reported to respond specifically to psychoactive cannabinoids, in particular, the
uptake of serotonin by mouse-brain synaptosomes and the inhibition of T-lymphocytic acyltransferase. The latter studies are extended
in the present paper to mouse-brain synaptosomal acyltransferase activity, which we have shown to be inhibited by Ag-THC given to
mice in single doses in vivo. The plasma membrane-bound enzyme acyl-CoA:lyso-phosphatidylcholine acyltransferase
(LPC-acyltransferase, is thought to be responsible for regulating the proportion of saturated fatty acids present in phosphatidylcholines
in the plasma membrane and may play an important role in the maintenance of membrane structure and integrity. It has been
demonstrated that this enzyme in mouse lymphocytes can be inhibited by A9-THC at low concentrations (K,= 0.35 pM). While other
lipids including psychoinactive cannabinoids are capable of perturbing membrane bilayers and at high concentrations can inhibit the
lymphocytic LPC-acyl-transferase, only Ag-THCcan inhibit enzyme at micro-molar concentrations.
In the present paper we demonstrate that a similar enzyme activity in mouse-brain synaptosomes is also inhibited by low levels of
psychoactive cannabinoids and that, while many lipid-soluble substances can inhibit the enzymes at high concentrations, in pro-
portion to their nonspecific ability to cause anesthesia, cannabinoids can inhibit the synaptosomal enzymes at much lower
concentrations in the order of their psychoactivity.
Molar volume correlations are used in this study to distinguish the nonspecific inhibition of the synaptosomal enzymes shown by all
lipid substances, in proportion to their ability to perturb lipid membranes, from the specific inhibition seen for psychoactive
cannabinoids. The ability of lipid-soluble molecules to induce anesthesia is known to be closely related to their molar volurnesls and to
their ability to protect erythrocytes against hypotonic lysis. Using molar volume correlations, the ability of cannabinoids and other
compounds to inhibit synaptosomal acyltransferase is compared with their ability to expand erythrocytic membranes.
The ability of a number of lipophilic compounds to inhibit the mouse-brain synaptosomal enzyme acyl coenzyme
Alysophosphatidylcholine acyltransferase has been measured in vitro. Psychoactive cannabinoids inhibit the enzyme at concentrations
much lower than is predicted from their capacity to act as lipid-soluble anesthetics. Nonpsychoactive cannabinoids do not show
specific inhibition. Molar volume relationships are used to show that, while all lipid-soluble molecules exert some inhibitory effect in
proportion to their ability to dissolve in biological membranes, psychoactive cannabinoids have an inhibitory effect greatly in excess of
their anesthetic potency. The isoprenoid convulsant thujone has been suggested to have psychoactivity similar to cannabinoids but
does not mimic the cannabinoids in inhibiting the synaptosomal enzyme. Molar volumes and specific interactions are used in
structure-activity correlations which yield information on the relative concentrations of hiophase in drug-responsive systems and the
specificity of membrane-active drugs.
Introduction
The psychoactive constituents of marihuana are the cannabinoids, the principal component being (-)-trans-A9-tetrahydrocannabinol
(A9-THC). A variety of other natural and synthetic cannabinoids of varying psychoactive potencies which depend on side-chain
substitutions and ring modifications have been described. One explanation of cannabinoid psychoactivity that has gained wide
acceptance is the "partial anesthetic" hypothesis and is based on the ability of cannabinoids to cause membrane perturbations similar
to those seen for many lipid-soluble anesthetics. We report here the inhibition of a membrane-bound enzyme in synaptosomes by
psychoactive
cannabinoids at concentrations well below those required to produce nonspecific anesthetic effects or molar volume dependent
membrane perturbations.
The high lipid solubility of the cannabinoids would suggest that their action be at least partly mediated at the level of cell membranes. A
variety of nonspecific effects on cannabinoids on cell membrane processes have been described, including inhibition of lymphocytic
transformation,lysosomal lysis, mitochondrial disruption, and the uptake of putative neurotransmitters by mouse-brain synaptosomes.
Recently some membrane processes have been reported to respond specifically to psychoactive cannabinoids, in particular, the
uptake of serotonin by mouse-brain synaptosomes and the inhibition of T-lymphocytic acyltransferase. The latter studies are extended
in the present paper to mouse-brain synaptosomal acyltransferase activity, which we have shown to be inhibited by Ag-THC given to
mice in single doses in vivo. The plasma membrane-bound enzyme acyl-CoA:lyso-phosphatidylcholine acyltransferase
(LPC-acyltransferase, is thought to be responsible for regulating the proportion of saturated fatty acids present in phosphatidylcholines
in the plasma membrane and may play an important role in the maintenance of membrane structure and integrity. It has been
demonstrated that this enzyme in mouse lymphocytes can be inhibited by A9-THC at low concentrations (K,= 0.35 pM). While other
lipids including psychoinactive cannabinoids are capable of perturbing membrane bilayers and at high concentrations can inhibit the
lymphocytic LPC-acyl-transferase, only Ag-THCcan inhibit enzyme at micro-molar concentrations.
In the present paper we demonstrate that a similar enzyme activity in mouse-brain synaptosomes is also inhibited by low levels of
psychoactive cannabinoids and that, while many lipid-soluble substances can inhibit the enzymes at high concentrations, in pro-
portion to their nonspecific ability to cause anesthesia, cannabinoids can inhibit the synaptosomal enzymes at much lower
concentrations in the order of their psychoactivity.
Molar volume correlations are used in this study to distinguish the nonspecific inhibition of the synaptosomal enzymes shown by all
lipid substances, in proportion to their ability to perturb lipid membranes, from the specific inhibition seen for psychoactive
cannabinoids. The ability of lipid-soluble molecules to induce anesthesia is known to be closely related to their molar volurnesls and to
their ability to protect erythrocytes against hypotonic lysis. Using molar volume correlations, the ability of cannabinoids and other
compounds to inhibit synaptosomal acyltransferase is compared with their ability to expand erythrocytic membranes.
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