Posts Tagged ‘THC’

In 1992 Devane isolates some lipidic substances from pig’s brain extracts, the N-arachidonoylethanolamine, called anandamide, that binds the cannabinoid receivers CB1 and CB2 and induces the pharmacological effects of Δ9-THC. Anandamide (AEA) was the first of a series of five endogenous agonists of the cannabinoid receivers that may be found in the brain and others tissues, as omo-gammalinoleic and docosatetraenoleic acid ethanolamides, 2-arachidonilglycerol (2AG) and noladinether. AEA and 2-AG surely are the best characterized.

Endocannabinoids Biosynthesis

If endogenous molecules hold a role in physiological answers, adjustable biosynthetic ways must exist in the cells, that is molecular mechanisms in a position to synthesize these substances at the opportune time and place. Moreover, the chemical marks carried by such molecules must be able to be finished, in case its biological function get exhausted, through also adjustable catabolic ways.

The involvement of endocannabinoids in the modulation of physiological functions both in nervous system and in peripheral tissues, today is confirmed by the discovery of specific mechanisms of biosynthesis and degradation. Both anandamide and 2-AG are synthesized starting from phospholipids forerunners and inactivated by means of the cells re-uptake and successive reactions of hydrolysis and/or esterification. In particular, anandamide is produced from the hydrolysis of the N-arachidonil-phosphatidilethanolamine (NArPE), process catalysed from a type-D phospholipase. NArPE, in its turn, is produced by a N-trans-acylation of the obtained phosphatidiletanolame capturing an arachidonic acid radical from the sn-1 position of other phospholipids, the last reaction is activated by calcium ions.

On the other hand 2-AG is produced thanks to the enzymatic and enantioselective hydrolysis of diacylglycerols through the enzyme sn-1 diacylglycerol-lipase. Diacylglycerols involved in 2-AG biosynthesis can be obtained by the hydrolysis of the fosfatidilinositol catalysed by a type C phospholipase, or by the fosfatidic acid one, catalysed by a specific phosphoidrolase.

Biological Action

Theirs biosynthetic mechanisms differentiate endocannabinoids from other neuromodulators as acetylcholine, glutamate or noradrenaline, that are pre-synthetized and conserved in secretory vesicles that discharge their content when the cell is appropriately stimulated. In this case the appropriate stimulus (for example the calcium ions (Ca2+) entry in the cell) determinates the beginning of anandamide and 2-AG synthesis starting from phospholipidics precursors likely contained presumabilly in the cell membrane; only at that time they are discharged outside the cell. This mechanism renders endocannabinoids similar to other arachidonic acid bioactive derivates, such as prostaglandins. Once synthetized, endocannabinoids bind to the THC receivers situated on adjacecent cells or on the same cell that produced them, therefore acting like paracrine or autocrine mediators. Because of their chemical nature, barely water-soluble, their easy spread in the extracellular matrix or in the blood is prevented. The bond with CB1 or CB2 receptors produces the beginning of successive cannabimimetic trasductional events ( for example the inhibition of the of cyclic AMP synthesis or the calcium ions (Ca2+) entry in the cell ).

The ending of endocannabinoids biological action takes place thanks to base the following mechanisms:

1. Cellular reuptake (in the anandamide case it’s facilitated by membrane carriers)
2. Enzymatic hydrolysis
3. Riesterification of the products of the hydrolysis in membrane phospholipids (2-AG, it also riesterificated before its enzymatic hydrolysis).

FAAH enzyme – mechanism of action

[lang_en-en]The enzyme that catalyzes the hydrolysis of the anandamide has been characterized and called “fatty acid amide hydrolase” (FAAH). In some conditions such enzyme catalyzes also the hydrolysis of the 2-AG, for which, however, other “more or less selective” hydrolase also exist. Such molecules can serve as base for the development of new therapeutic agents to use for the treatment of those pathologies caused or gotten worse from an excessive expression of the inactivation mechanisms or a defective operation of the biosynthetic mechanisms of the endocannabinoids.

The studies on the possible mechanism of action of derivatives of the Cannabis and, of consequence, on their own prospective therapeutic applications, endured an unexpected acceleration with the discovery of specific receptors for the THC and endogenous ligands for such proteins.

Cannabinoid receptor structure. Taken from Italian wikipedia article.

Up to now two types of receptors for the THC and its synthetic derivates have been characterized: CB1 receptor, discovered in 1990, mostly expressed in the nervous system and some peripheral tissue, and CB2 receptor, singled out for the first time in 1993 and till now identified only in the immune system cells of the mammals.

To the discovery of CB1 receptor immediately followed up, in 1992, the isolation, from the pig’s brain, of the first endogenous compound in a position to tying itself selective to such protein: it was the amide formed by ethanolamin and arachidonic acid, two ubiquitous components of animal cellular membranes, called “anandamide” (from the Sanskrit word “ananda” that means “inner serenity”).

Subsequently others two structural analogous of the “anandamide” were isolated still from the pig’s brain, while another type of molecule, pertaining to the class of metabolic intermediates known as monoacylglycerols, was identified in peripheral tissues and set as CB2 receptor ligand: 2-arachidonoyl-glycerol (2-AG).

Afterwards anandamide and its analogous were discovered to preferentially activate CB1 receptor, while 2-AG, that it is also present in mammals brain, can indifferently activate both types of receptors for THC.

The discovery of receptors for the THC and endogenous molecules in a position to activating such proteins, simulating therefore in great part the typical Cannabis psychotropic effects, demonstrated the existence of an endogenous cannabinoid system whose physiological role is still a debate subject, and whose future study will be able to carry to the understanding of molecular mechanisms that are the base of the abuse of chemical compounds contained in the Indian hemp, and to developing, on the base of the well known therapeutic properties of such plant, new drugs high therapeutic potential for the treatment of the nervous, immune and cardiovascular system diseases.

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