Tag Archives: cannabinoid receptors

Peripherally restricted CB1 receptor blockers.

Posted on by

“Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease.

These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists.

Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed.

Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).”

http://www.ncbi.nlm.nih.gov/pubmed/23902803

Anandamide, Cannabinoid Type 1 Receptor, and NMDA Receptor Activation Mediate Non-Hebbian Presynaptically Expressed Long-Term Depression at the First Central Synapse for Visceral Afferent Fibers.

Posted on by

“Presynaptic long-term depression (LTD) of synapse efficacy generally requires coordinated activity between presynaptic and postsynaptic neurons and a retrograde signal synthesized by the postsynaptic cell in an activity-dependent manner.

In this study, we examined LTD in the rat nucleus tractus solitarii (NTS), a brainstem nucleus that relays homeostatic information from the internal body to the brain.

We found that coactivation of N-methyl-D-aspartate receptors (NMDARs) and type 1 cannabinoid receptors (CB1Rs) induces LTD at the first central excitatory synapse between visceral fibers and NTS neurons. This LTD is presynaptically expressed. However, neither postsynaptic activation of NMDARs nor postsynaptic calcium influx are required for its induction. Direct activation of NMDARs triggers cannabinoid-dependent LTD.  In addition, LTD is unaffected by blocking 2-arachidonyl-glycerol synthesis, but its induction threshold is lowered by preventing fatty acid degradation.

Altogether, our data suggest that LTD in NTS neurons may be entirely expressed at the presynaptic level by local anandamide synthesis.”

http://www.ncbi.nlm.nih.gov/pubmed/23904599

Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism.

Posted on by

“Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Delta(9)-tetrahydrocannabinol (Delta(9)-THC)…

In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Delta(9)-THC…

Cannabidiol potentiated pharmacological effects of Delta(9)-THC via CB(1) receptor-dependent mechanism.

These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.”

http://www.ncbi.nlm.nih.gov/pubmed/18021759

Cannabis-Linked Cell Receptor Might Help Prevent Colon Cancer

Posted on by

“A cannabinoid receptor lying on the surface of cells may help suppress colorectal cancer, say U.S. researchers. When the receptor is turned off, tumor growth is switched on. Cannabinoids are compounds related to the tetrahydrocannabinol (THC) found in the cannabis plant.”

Photo of colon composite

“It’s already known that the receptor, CB1, plays a role in relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. This study suggests that CB1 may offer a new path for cancer prevention or treatment.”

More: http://www.medicinenet.com/script/main/art.asp?articlekey=91511

Cannabis compound clue to colon cancer

Posted on by

“…taking substances similar to those found in cannabis might one day help to treat colon cancer.

Raymond DuBois and colleagues at the University of Texas, Houston, discovered that a key receptor for cannabinoids – compounds similar to the active ingredient of cannabis – is turned off in most types of human colon cancer cells.

 Similarly, mice genetically engineered to develop colon tumours developed more of them if the receptor, called CB1, was knocked out What’s more, tumours shrank when the genetically engineered mice were injected with a cannabinoid.

One suggestion is that lack of CB1 encourages tumour growth because the receptor normally interacts with cannabinoids made by the body to prompt cells to die. This opens up a possible two-step treatment for colon cancer…”

http://www.newscientist.com/article/mg19926685.000-cannabis-compound-clue-to-colon-cancer.html

Cannabis-Linked Cell Receptor Might Help Prevent Colon Cancer – TheWashingtonPost

Posted on by

“A cannabinoid receptor lying on the surface of cells may help suppress colorectal cancer, say U.S. researchers. When the receptor is turned off, tumor growth is switched on.

Cannabinoids are compounds related to the tetrahydrocannabinol (THC) found in the cannabis plant.

It’s already known that the receptor, CB1, plays a role in relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. This study suggests that CB1 may offer a new path for cancer prevention or treatment.”

More: http://articles.washingtonpost.com/2008-08-01/news/36873908_1_colorectal-cancer-tumor-growth-smaller-tumors

Cannabinoid cell surface receptor plays a tumor-suppressing role in human colorectal cancer

Posted on by

“New preclinical research shows that cannabinoid cell surface receptor CB1 plays a tumor-suppressing role in human colorectal cancer, scientists report in the Aug. 1 edition of the journal Cancer Research.

CB1 is well-established for relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. It now may serve as a new path for cancer prevention or treatment.

“We’ve found that CB1 expression is lost in most colorectal cancers, and when that happens a cancer-promoting protein is free to inhibit cell death,” said senior author Raymond DuBois, M.D., Ph.D., provost and executive vice president of The University of Texas M. D. Anderson Cancer Center.

DuBois and collaborators from Vanderbilt-Ingram Cancer Center also show that CB1 expression can be restored with an existing drug, decitabine. They found that mice prone to developing intestinal tumors that also have functioning CB1 receptors develop fewer and smaller tumors when treated with a drug that mimics a cannabinoid receptor ligand. Ligands are molecules that function by binding to specific receptors. Agonists are synthetic molecules that mimic the action of a natural molecule.

“Potential application of cannabinoids as anti-tumor drugs is an exciting prospect, because cannabinoid agonists are being evaluated now to treat the side-effects of chemotherapy and radiation therapy,” DuBois said. “Turning CB1 back on and then treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention.”

Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the body internally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, most famously the active ingredient in marijuana (THC).”

More: http://www.news-medical.net/news/2008/08/03/40485.aspx

Active Chemicals in Cannabis Inhibits Prostate Cancer Cell Growth

Posted on by

“According to researchers, active chemicals in cannabis inhibits prostate cancer cell growth…

cannabis

Professor Ines Diaz-Laviada, study author said: “Our research shows that there are areas on prostate cancer cells which can recognize and talk to chemicals found in cannabis called cannabinoids. These chemicals can stop the division and growth of prostate cancer cells and could become a target for new research into potential drugs to treat prostate cancer.””  http://www.elements4health.com/active-chemicals-in-cannabis-inhibits-prostate-cancer-cell-growth.html

“Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2″ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743360/

“Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism.” http://www.ncbi.nlm.nih.gov/pubmed/10570948

Activation of spinal cannabinoid cb2 receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice.

Posted on by

“The role of spinal cannabinoid systems in neuropathic pain of streptozotocin-induced diabetic mice was studied…

 … A low dose of WIN-55,212-2  significantly recovered the tail-flick latency in streptozotocin-induced diabetic mice… The selective cannabinoid CB2 receptor agonist L-759,656 also dose-dependently recovered the tail-flick latency in streptozotocin-induced diabetic mice…

 These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB2 receptor agonists might have an ability to recover diabetic neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/23892011

Hepatic Cannabinoid Receptor Type 1 Mediates Alcohol-Induced Regulation of Bile Acid Enzyme Genes Expression Via CREBH.

Posted on by

“In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process.

We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo along with significant increase in Crebh gene expression and activation.

 Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis…

 Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis.”

http://www.ncbi.nlm.nih.gov/pubmed/23894352