Gourt Home::Gourt :: Cannabinoid receptor
The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids.
Classification
There are currently two known subtypes, CB1Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346: 561-4. PMID 2165569Gerard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 1991; 279 (Pt1):129-34. PMID 1718258 which is expressed mainly in the brain, but also in the lungs, liver and kidneys and CB2 which is mainly expressed in the immune system and in hematopoietic cells. Mounting evidence suggests that there are novel cannabinoid receptorsBegg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo FM, Liu J, KunosG. Evidence for novel cannabinoid receptors. Pharmacol Ther 2005; 106:133–145. PMID 15866316 that is, non-CB1 and non-CB2, which are expressed in endothelial and CNS. However, these have not been cloned yet.
The protein sequences of CB1 and CB2 receptors are about 45% similar. In addition, minor variations in each receptor have been identified. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. The affinity of an individual cannabinoid to each receptor determines the effect of that cannabinoid. Cannabinoids that bind more selectively to certain receptors are more desirable for medical usage.
Expression
CB1
CB1 receptors are thought to be the most widely expressed G-protein coupled receptors in the brain. Varying levels of expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei and other subcortical regions (e.g. the septal region), cerebellar cortex, and brainstem nuclei (e.g. the periaqueductal gray)Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27: 73-100. PMID 16306385.CB1 is expressed on several cell types of the pituitary gland, in the thyroid gland, and probably in the adrenal glandPagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27: 73-100. PMID 16306385.
CB1 is also expressed in several cells relating to metabolism, such as fatt cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tractPagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27: 73-100. PMID 16306385. It is also expressed in the lungs and the kidney.
CB1 is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua and placenta. It is probably important also for the embryoPagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27: 73-100. PMID 16306385.
CB2
CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also has a function in keratinocytes, and are expressed on mouse pre-implantation embryos. It is also expressed on peripheral nerve terminals.Physiology
Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (=endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.
After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK)Demuth DG, Molleman A. Cannabinoid signalling. Life Sci 2006; 78: 549-63. PMID 16109430. However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many morePagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27: 73-100. PMID 16306385.
Cannabis sativa preparations have been known as therapeutic agents against various diseases for millennia. The native active constituent, Delta 9-tetrahydrocannabinol (delta-9-THC) was found to be the principal mediator of the effects of cannabisGaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964; 86: 1646– 1647. Δ9-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients.
Separation between the therapeutically undesirable psychotropic effects ,and the clinically desirable ones however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors —anandamide and 2-arachidonylglycerol (2-AG)— produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. While the effects mediated by CB1, mostly in the CNS, have been thoroughly investigated, those mediated by CB2 are not equally well defined.
Inhibition of gastrointestinal activity has been observed after administration of Delta 9-THC, or of anandamide. This effect has been assumed to be CB1-mediated since the specific CB1 antagonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB2-mediated component.
Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension. Anandamide and 2-AG, produced by macrophages and platelets respectively, may mediate this effect.
The hypotension in hemorrhaged rats was prevented by the CB1 antagonist SR 141716A. Recently the same group found that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR 141716A-sensitive "anandamide receptor," distinct from the CB1 cannabinoid receptor, and that activation of such a receptor by an endocannabinoid, possibly anandamide, contributes to endotoxin-induced mesenteric vasodilation in vivo. The highly potent synthetic cannabinoid HU-210, as well as 2-AG, had no mesenteric vasodilator activity. Furthermore it was shown that mesenteric vasodilation by anandamide apparently has 2 components, one mediated by a SR 141716-sensitive non-CB1 receptor (located on the endothelium) and the other by an SR 141716A-resistant direct action on vascular smooth muscle.
The production of 2-AG is enhanced in normal, but not in endothelium-denuded rat aorta on stimulation with Carbachol, an acetylcholine receptor agonist. 2-AG potently reduces blood pressure in rats and may represent an endothelium-derived hypotensive factor.
Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage. This effect is produced by interaction with CB1 (or CB1-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitylethanolamide, which like anandamide is present in the [[skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitylethanolamide, however does not bind to either CB1 or CB2. Its analgetic activity is blocked by the specific CB2 antagonist SR 144528, though not by the specific CB1 antagonist SR 141716A. Hence a CB2-like receptor was postulated.
U.S. Pat. No. 5,434,295 discloses a family of novel 4-phenyl pinene derivatives, and teaches how to use those compounds in pharmaceutical compositions useful for treating various pathological conditions associated with damage to the central nervous system. U.S. Pat. No. 4,282,248 discloses additional pinene derivatives. These patents do not mention that any of the disclosed compounds are selective for peripheral cannabinoid receptors.
Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher affinity than to the CB1 receptor. Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB1/CB2 binding ratio > 1000. The pharmacology of those known agonists has yet to be described.
Certain tumors, especially gliomas, express CB2 receptors. Guzman and coworkers have shown that delta-9-tetrahydrocannabinol and WIN-55,212-2, two non-selective cannabinoid agonists, induce the regression or eradication of malignant brain tumors in rats and mice et al., Nature Medicine 6, 313-319, (2000). The rat glioma C6 expresses the CB2 receptor and, on the basis of studies with CB1 and CB2 selective antagonists, it has been proposed that activation of either of the two receptors may trigger apoptosis.
Thus, there is a need for selective peripheral cannabinoid receptors and particularly for specific agonists of the peripheral cannabinoid receptor CB2. The present invention now satisfies that need.
References
- Hanus L. el al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14228-33. PMID 10588688. Full text
"Cannabinoid receptor"