Category Archives: Uncategorized

Cannabinoids biology: the search for new therapeutic targets.

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“Cannabinoids, in the form of marijuana plant extracts, have been used for thousands of years for a wide variety of medical conditions, ranging from general malaise and mood disorders to more specific ailments, such as pain, nausea, and muscle spasms.

The discovery of tetrahydrocannabinol, the active principal in marijuana, and the identification and cloning of two cannabinoid receptors (i.e., CB1 and CB2) has subsequently led to biomedical appreciation for a family of endocannabinoid lipid transmitters.

The biosynthesis and catabolism of the endocannabinoids and growing knowledge of their broad physiological roles are providing insight into potentially novel therapeutic targets.

Compounds directed at one or more of these targets may allow for cannabinoid-based therapeutics with limited side effects and abuse liability.”

http://www.ncbi.nlm.nih.gov/pubmed/16809476

Cannabinoid system in the skin – a possible target for future therapies in dermatology.

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“Cannabinoids and their derivatives are group of more than 60 biologically active chemical agents, which have been used in natural medicine for centuries.

The major agent of exogenous cannabinoids is Delta(9)-tetrahydrocannabinol (Delta(9)-THC), natural psychoactive ingredient of marijuana.

Recent discoveries of endogenous cannabinoids (e.g. arachidonoylethanolamide, 2-arachidonoylglycerol or palmithyloethanolamide) and their receptors initiated discussion on the role of cannabinoid system in physiological conditions as well as in various diseases.

Based on the current knowledge, it could be stated that cannabinoids are important mediators in the skin, however their role have not been well elucidated yet.

In our review, we summarized the current knowledge about the significant role of the cannabinoid system in the cutaneous physiology and pathology, pointing out possible future therapeutic targets.”

http://www.ncbi.nlm.nih.gov/pubmed/19664006

Cannabis in Eurasia: origin of human use and Bronze Age trans-continental connections

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Vegetation History and Archaeobotany

“A systematic review of archaeological and palaeoenvironmental records of cannabis (fibres, pollen, achenes and imprints of achenes) reveals its complex history in Eurasia. A multiregional origin of human use of the plant is proposed, considering the more or less contemporaneous appearance of cannabis records in two distal parts (Europe and East Asia) of the continent. A marked increase in cannabis achene records from East Asia between ca. 5,000 and 4,000 cal bpmight be associated with the establishment of a trans-Eurasian exchange/migration network through the steppe zone, influenced by the more intensive exploitation of cannabis achenes popular in Eastern Europe pastoralist communities. The role of the Hexi Corridor region as a hub for an East Asian spread of domesticated plants, animals and cultural elements originally from Southwest Asia and Europe is highlighted. More systematic, interdisciplinary and well-dated data, especially from South Russia and Central Asia, are necessary to address the unresolved issues in understanding the complex history of human cannabis utilisation.”

http://link.springer.com/article/10.1007%2Fs00334-016-0579-6

“The Tantalizing Clues That Suggest Cannabis Played a Key Role in the Birth of Civilization Itself” http://theinfluence.org/the-tantalizing-clues-that-suggest-cannabis-played-a-key-role-in-the-birth-of-civilization-itself/

“Stoned age: Humans were getting high on cannabis 10,000 years ago and experts say they also used the drug for food and clothes

“Man’s Stoned Age: cannabis use began 10,000 years ago. After the Ice Age came the Stoned Age. Early humans began using cannabis as long as 10,000 years ago, just as Europe’s glaciers had started their final retreat, scientists have found. An archaeological study suggests early humans in Europe and Asia stumbled on the plant at roughly the same time. The discovery was valued, suggest the scientists, not just for its psychoactive properties but also because its nutritious seeds could quench hunger pangs and hemp fibres could be woven into clothing.”                         http://www.thetimes.co.uk/article/mans-stoned-age-cwvtj2js2

“Founders of Western civilisation were prehistoric dope dealers”  https://www.newscientist.com/article/2096440-founders-of-western-civilisation-were-prehistoric-dope-dealers/

The cannabinoids: therapeutic potentials.

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“A review of the therapeutic potentials of the cannabinoids is presented. With respect to the antifertility aspects of cannabinoids, 2 mg delta 9-THC suppressed luteinizing hormone secretion in rats and 2 and 3 mg/kg resulted in a deterioation of male sexual performance. A new chapter in marijuana research was opened in 1964 with the identification of delta 9-tetrahydrocannabinol as the active ingredient. Antiedema, analgesic, antipyretic, antiinflammatory, antifertility, antiepileptic, anticonvulsant, antihypertensive, cardiotonic, pulmonary, and antidepressant effects along with potentiation of barbiturates and analgesics are reviewed leading one to the conclusion that marijuana is “a drug for all reasons”. During the past decade many investigators have pursued the possibility of modification of the delta 9 structure to delineate activities. 1 compound, Abbott 40656, SP106, a water-soluble benzopyran derivative is presently under Phase 1 clinical evaluation as a sedative-hypnotic.”

http://www.ncbi.nlm.nih.gov/pubmed/12307093/

Type-2 Cannabinoid Receptors in Neurodegeneration.

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“Based on its wide expression in immune cells, type 2 cannabinoid (CB2) receptors were traditionally thought to act as “peripheral receptors” with an almost exclusively immunomodulatory function. However, their recent identification in mammalian brain areas, as well as in distinct neuronal cells, has opened the way to a re-consideration of CB2 signaling in the context of brain pathophysiology, synaptic plasticity and neuroprotection. To date, accumulated evidence from several independent preclinical studies has offered new perspectives on the possible involvement of CB2signaling in brain and spinal cord traumatic injury, as well as in the most relevant neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease and Huntington’s chorea. Here, we will review available information on CB2 in these disease conditions, along with data that support also its therapeutic potential to treat them.”

http://www.ncbi.nlm.nih.gov/pubmed/27450295

Discovery of novel Tetrahydrobenzo[b]thiophene and pyrrole based scaffolds as potent and selective CB2 receptor ligands: The structural elements controlling binding affinity, selectivity and functionality.

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“CB2-based therapeutics show strong potential in the treatment of diverse diseases such as inflammation, multiple sclerosis, pain, immune-related disorders, osteoporosis and cancer, without eliciting the typical neurobehavioral side effects of CB1 ligands.

For this reason, research activities are currently directed towards the development of CB2 selective ligands. Herein, the synthesis of novel heterocyclic-based CB2 selective compounds is reported.

The present findings thus pave the way to the design and optimization of heterocyclic-based scaffolds with lipophilic carboxamide and/or retroamide substituent that can be exploited as potential CB2 receptor activity modulators.”

http://www.ncbi.nlm.nih.gov/pubmed/27448919

Allosteric modulation of heterodimeric G-protein-coupled receptors.

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“G-protein-coupled receptors (GPCRs) are, and will probably remain, the most tractable class of targets for the development of small-molecule therapeutic medicines.

Currently, all approved GPCR-directed medicines are agonists or antagonists at orthosteric binding sites – except for the calcimimetic cinacalcet, which is a positive allosteric modulator of Ca(2+)-sensing receptors, and maraviroc, an allosteric inhibitor of CC-chemokine receptor (CCR) 5.

It is now widely accepted that GPCRs exist and might function as dimers, and there is growing evidence for the physiological presence and relevance of GPCR heterodimers.

Molecules that can regulate a GPCR within a heterodimer, through allosteric effects between the two protomers of the dimer or between a protomer or protomers and the associated G protein, offer the potential to function in a highly selective and tissue-specific way.

Despite the conceptual attraction of such allosteric regulators of GPCR heterodimers as drugs, they cannot be identified by screening approaches that routinely use a ‘one GPCR target at a time’ strategy.

In our opinion, this will require the development of new approaches for screening and a return to the use of physiologically relevant cell systems at an early stage in compound identification.”

http://www.ncbi.nlm.nih.gov/pubmed/18022255

Allosteric modulation of the cannabinoid CB1 receptor.

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“We investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)-ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB1 receptor.

These data suggest that the Org compounds bind allosterically to the CB1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site.

The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.”

http://www.ncbi.nlm.nih.gov/pubmed/16113085

Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors.

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“The mechanism of action of cannabidiol, one of the major constituents of cannabis, is not well understood but a noncompetitive interaction with mu opioid receptors has been suggested on the basis of saturation binding experiments.

The aim of the present study was to examine whether cannabidiol is an allosteric modulator at this receptor, using kinetic binding studies, which are particularly sensitive for the measurement of allosteric interactions at G protein-coupled receptors.

In addition, we studied whether such a mechanism also extends to the delta opioid receptor. For comparison, (-)-Delta9-tetrahydrocannabinol (THC; another major constituent of cannabis) and rimonabant (a cannabinoid CB1 receptor antagonist) were studied.

The present study shows that cannabidiol is an allosteric modulator at mu and delta opioid receptors. This property is shared by THC but not by rimonabant.”

http://www.ncbi.nlm.nih.gov/pubmed/16489449

Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors.

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“Microglial cells, the macrophages of the brain, express low, yet detectable levels of cannabinoid CB(1) receptors, which are known to modulate cell migration.

To determine if cannabinoid CB(1) receptors expressed by microglial cells modulate their migration, we assessed whether arachidonylcyclopropylamide (ACPA, an agonist shown to selectively activate CB(1) receptors) affects the migration of BV-2 cells, a mouse microglial cell line.

Our results suggest that cannabinoid CB(2) receptors and abn-CBD receptors, rather than cannabinoid CB(1) receptors, regulate microglial cell migration, and that ACPA is a broad cannabinoid receptor agonist.”

http://www.ncbi.nlm.nih.gov/pubmed/12921861