“Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically, and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. Compound A is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound A eyedrops were well tolerated and generated an IOP-lowering trend, but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound A prodrugs that are efficiently metabolized to the parent compound, for improved solubility and ocular permeability, while maintaining low systemic exposures.”
Category Archives: Endocannabinoid System
Phytocannabinoids
“Phytocannabinoids, also called ”natural cannabinoids”, ”herbal cannabinoids”, and ”classical cannabinoids”, are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.
In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odour of the cannabis plant.
Phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols, they form more water-soluble phenolate salts under strongly alkaline conditions.
All-natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).
Types
At least 66 cannabinoids have been isolated from the cannabis plant. To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:
- CBG Cannabigerol
- CBC Cannabichromene
- CBL Cannabicyclol
- CBV Cannabivarin
- THCV Tetrahydrocannabivarin
- CBDV Cannabidivarin
- CBCV Cannabichromevarin
- CBGV Cannabigerovarin
- CBGM Cannabigerol Monoethyl Ether
Tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. It appears to ease moderate pain (analgetic) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral.
”Delta”-9-Tetrahydrocannabinol (Δ9-THC, THC) and ”delta”-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the ”high” associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.
Cannabidiol
Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC. However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms.
This is supported by psychological tests, in which participants experience less intense psychotic effects when intravenous THC was co-administered with CBD (as measured with a PANSS test).
It has been hypothesized that CBD acts as an allosteric antagonist at the CB1 receptor and thus alters the psychoactive effects of THC.
It appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.
Cannabigerol
Cannabigerol (CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.
Tetrahydrocannabivarin
Tetrahydrocannabivarin (THCV) is prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.
Cannabichromene
Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC It is found in nearly all tissues in a wide range of animals.
Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and ”homo”-γ-linolenoylethanolamine, have similar pharmacology.
All of these are members of a family of signalling lipids called ”N”-acylethanolamides, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamine, which possess anti-inflammatory and orexigenic effects, respectively. Many ”N”-acylethanolamines have also been identified in plant seeds and in molluscs.
- 2-arachidonoyl glycerol (2-AG)
Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both, and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling ”in vivo”.
In particular, one ”in vitro” study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.
- 2-arachidonyl glyceryl ether (noladin ether)
In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain.
Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at “any appreciable amount” in the brains of several different mammalian species.
It binds to the CB1 cannabinoid receptor (”K”i = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and only weakly to the CB2 receptor.
Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.
- Virodhamine (OAE)
A fifth endocannabinoid, virodhamine, or ”O”-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist ”in vivo”.
In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.
Function
Endocannabinoids serve as intercellular ‘lipid messengers’, signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells.
Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling.
Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized ‘on-demand’ rather than made and stored for later use.
The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
The endocannabinoid 2-AG has been found in bovine and human maternal milk.
Retrograde signal
Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively.
Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow.
They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released.
Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released.
This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic.
The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled.
For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell.
On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Range
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
Other thoughts
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
”Scientific American” published an article in December 2004, entitled “The Brain’s Own Marijuana” discussing the endogenous cannabinoid system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body.
U.S. Patent # 6630507
In 2003 The U.S.A.’s Government as represented by the Department of Health and Human Services was awarded a patent on cannabinoids as antioxidants and neuroprotectants. U.S. Patent 6630507.”
Cannabinoid Receptors
“Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors.
The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.
These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles.
At present, there are two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more.
Cannabinoid receptor type 1
CB1 receptors are found primarily in the brain, to be specific in the basal ganglia and in the limbic system, including the hippocampus.
They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
Cannabinoid receptor type 2
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen.
While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.
CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.”
http://www.news-medical.net/health/Cannabinoid-Receptors.aspx
Cannabis News: The Cannabinoid System Reverses Dementia, Treats PTSD and Controls Diabetes Top May’s News Digest from Publius
“The Cannabinoid System’s role in reversing dementia, treating PTSD and controlling diabetes highlight May’s cannabis news from Publius, the pen name used by the authors of The Cannabis Papers – Federal ignorance goes on unabated.”
“The Cannabinoid System’s (CS) role in reversing dementia, treating PTSD and controlling diabetes highlight May’s cannabis news from Publius, the pen name used by the authors of The Cannabis Papers: A citizen’s guide to cannabinoids (2011).”
More: http://www.prweb.com/releases/2013/5/prweb10787154.htm
Dysregulation of Cannabinoid CB1 Receptor and Associated Signaling Networks in Brains of Cocaine Addicts and Cocaine-Treated Rodents.
The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, receptor regulatory kinases (GRK), and associated signaling (mTOR and p70S6K) in brain cortex of drug abusers and cocaine- and cannabinoid-treated rodents…
In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB1 receptor signaling was dampened. The dysregulation of CB1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts.”
Cannabinoid receptor systems: therapeutic targets for tumour intervention.
“The past decade has witnessed a rapid expansion of our understanding of the biological roles of cannabinoids and their cognate receptors. It is now certain that Delta9-tetrahydrocannabinol, the principle psychoactive component of the Cannabis sativa plant, binds and activates membrane receptors of the 7-transmembrane domain, G-protein-coupled superfamily.
Several putative endocannabinoids have since been identified, including anandamide, 2-arachidonyl glycerol and noladin ether. Synthesis of numerous cannabinomimetics has also greatly expanded the repertoire of cannabinoid receptor ligands with the pharmacodynamic properties of agonists, antagonists and inverse agonists.
Collectively, these ligands have proven to be powerful tools both for the molecular characterisation of cannabinoid receptors and the delineation of their intrinsic signalling pathways. Much of our understanding of the signalling mechanisms activated by cannabinoids is derived from studies of receptors expressed by tumour cells; hence, this review provides a succinct summary of the molecular pharmacology of cannabinoid receptors and their roles in tumour cell biology.
Moreover, there is now a genuine expectation that the manipulation of cannabinoid receptor systems may have therapeutic potential for a diverse range of human diseases. Thus, this review also summarises the demonstrated antitumour actions of cannabinoids and indicates possible avenues for the future development of cannabinoids as antitumour agents.” http://www.ncbi.nlm.nih.gov/pubmed/14640910
The endocannabinoid system and its therapeutic exploitation.
“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.” http://www.ncbi.nlm.nih.gov/pubmed/15340387
Cannabinoids.
“Since the discovery of an endogenous cannabinoid system, research into the pharmacology and therapeutic potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled cannabinoid receptors, CB(1) and CB(1), have been cloned and several putative endogenous ligands (endocannabinoids) have been detected during the past 15 years. The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), derivatives of arachidonic acid, that are produced “on demand” by cleavage of membrane lipid precursors.
Besides phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic agonists and antagonists at the CB receptors and inhibitors of endocannabinoid degradation. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues, including immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart. There is evidence for some non-receptor dependent mechanisms of cannabinoids and for endocannabinoid effects mediated by vanilloid receptors.
Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson’s disease and memory impairment in Alzheimer’s disease.”
[The endocannabinoid system].
“The endocannabinoid system is a physiological system, which is responsible for the control of glucose and lipid-metabolism, as well as for the regulation of the body weight.
The endocannabinoid receptors are distributed both in the central and peripher nervous system.
Different studies provide evidence that an hyperactive endocannabinoid system is involved in the development of different cardiovascular risk factors.
The pharmacological blockade of these cannabinoid receptors may represent a new approach for cardiometabolic risk management.””
Brain-Imaging Study Links Cannabinoid Receptors to Post-Traumatic Stress Disorder: First Pharmaceutical Treatment for PTSD Within Reach
“In a first-of-its-kind effort to illuminate the biochemical impact of trauma, researchers at NYU Langone Medical Center have discovered a connection between the quantity of cannabinoid receptors in the human brain, known as CB1 receptors, and post-traumatic stress disorder, the chronic, disabling condition that can plague trauma victims with flashbacks, nightmares and emotional instability…
CB1 receptors are part of the endocannabinoid system, a diffuse network of chemicals and signaling pathways in the body that plays a role in memory formation, appetite, pain tolerance and mood. Animal studies have shown that psychoactive chemicals such as cannabis, along with certain neurotransmitters produced naturally in the body, can impair memory and reduce anxiety when they activate CB1 receptors in the brain…
“There’s not a single pharmacological treatment out there that has been developed specifically for PTSD,” says Dr. Neumeister. “That’s a problem. There’s a consensus among clinicians that existing pharmaceutical treatments such as antidepressant simple do not work. In fact, we know very well that people with PTSD who use marijuana — a potent cannabinoid — often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications. Clearly, there’s a very urgent need to develop novel evidence-based treatments for PTSD.”
Read more: http://www.sciencedaily.com/releases/2013/05/130514085016.htm