Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Patent
1995-07-26
1997-04-08
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C07C23300
Patent
active
056189559
DESCRIPTION:
BRIEF SUMMARY
This appln is a 371 of PCT/US93/11625 filed Nov. 30, 1993.
FIELD OF THE INVENTION
The invention relates to certain polyunsaturated fatty acid amides, and derivatives of these. Part of these are present in the brain, and part are products of synthesis. The novel pure compounds have a variety of pharmacological properties. They inhibit the specific binding of a cannabinoid probe to synaptosomal membranes. The compounds of the invention can be provided in radioactivity tagged form.
BACKGROUND OF THE INVENTION
Arachidonic acid ethanolamide (anandamide) and similar compounds are constituents of the brain. Anandamide and certain of the compounds similar with same, bind to the cannabinoid receptor. The binding of the ananamide to the cannabinoid receptor is similar to the binding of .DELTA..sup.9 -tetrahydrocannabinol. There exist in the body many mediators, which are derivatives of arachidonic acid, such as prostaglandins and leukotrienes, which are present as large families of related compounds. Certain of these do not bind to the cannabinoid receptor, and it was one of the aims of the present invention to provide and identify compounds which have pharmacological properties similar to the properties of anandamide.
The existence of a receptor and the high structural requirements for cannabinoid activity indicate the possible presence of a specific endogenous cannabinoid ligand.
SUMMARY OF THE INVENTION
Endogenous ligands for the cannabinoid receptor have not yet been identified. Arachidonylethanolamide, a new arachidonic acid derivative--named anandamide, was isolated from porcine brain. Its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. It inhibits the specific binding of a labelled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands, and produces a concentration-dependent inhibition of the electrically-evoked twitch response of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Similar compounds were synthesized and their pharma-cological properties were investigated.
.DELTA..sup.9 -Tetrahydrocannabinol (.DELTA..sup.9 -THC), the psychoactive constituent of Cannabis binds to a specific G-protein coupled receptor in the brain. Although the cannabinoid receptor in the rat and in the human has been cloned, its physiological function is unknown. The well established behavioral effects of THC and the abundance and anatomical localization of the receptor in the brain suggest a role for the receptor in the control of movement, memory, emotions and pain modulation, amongst other activities.
DESCRIPTION OF PREFERRED EMBODIMENTS
The existence of a receptor and the high structural requirements for cannabinoid activity indicate the possible presence of a specific endogenous cannabinoid ligand.
To screen for endogenous cannabinoid compounds there were tested brain-derived fractions using a centrifugation radioligand binding assay. Tritiated HU-243 (11-hydroxyhexahydrocannabinol-3-dimethylheptyl homolog) with a K.sub.D of 45 pM in rat synaptosomal membranes, was used as the probe. Organic soluble extracts of porcin brain were first chromatographed according to standard protocols for the separation of lipids. Pig brains were homogenized in chloroform and/or methanol and centrifuged at 13,000 x g. The organic soluble extract was fractionated over silica (Kieselgel 60, 70-230 mesh), following elution schemes used to separate the major classes of lipids [C. C. Sweeley, Methods Enzymol. 14, 254 (1969); J. C. Dittmer and M. A. Wells, ibid. p. 482]. Many of the initial fractions isolated from brain inhibited the binding of [.sup.3 H]HU-243 to the cannabinoid receptor. Particular attention was paid to the binding of [.sup.3 H]HU-243 to the siliconized polypropylene microfuge tubes in which the assay was conducted. Normally, about 15-20% of the added [.sup.3 ]HU-243 adheres to the microfuge tube, with the amount increasing slightly when unlabelled cannabinoid drugs displace the radioliga
REFERENCES:
patent: 4619938 (1986-10-01), Takahashi et al.
Fride et al, Chemical Abstracts, vol. 118, #15, 1993.
Beuer Aviva
Devane William A.
Hanus Lemir
Mechoulam Raphael
Carr Deborah D.
Geist Gary
Yissum Research Development Company of the Hebrew University of
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