Cannabinoids (Exogenous)
Drugs

Author: Francesco Licciardi
Date: 18/03/2009

Description

Historical Survey

The hemp plant ( Cannabis sativa ) has figured in human history for six millennia or more. Its use for medical and social purposes was probably preceded by exploitation of its fibres and food value.

The oldest extant Chinese pharmacopoeia shows that the plant has been known to be bioactive from the earliest of times, with descriptions of excessive consumption causing the seeing of devils.
Later works (dating from only 4000 years ago) describe it as being useful for a variety of disorders including malarial fever, constipation and rheumatic pains.
It was in Indo-Aryan culture that the psychoactive actions of cannabis made it a sacred plant. It was valued, amongst other uses, for treating fevers and gastrointestinal disorders, and was used as an appetite stimulant.

In modern times, most attention has been paid both to the psychoactive properties of the compound and to its possible utility in the control of pain, but it is clear that there are other targets for actions of cannabinoids, including the immune and the cardiovascular systems.

Attempts to isolate the active entities were pursued in the 1940s with some success but it was largely as a result of the research of Mechoulam that D9-tetrahydrocannabinol was identified as the active ingredient of the plant.

Chemical Structure

Cannabinoids have been divided into four structural chemical groups: fatty acid derivatives or endocannabinoids, classical cannabinoids’ (tricyclic dibenzopyran derivatives), non-classical cannabinoids (bicyclic and tricyclic analogues of D9-tetrahydrocannabinol), and alkylaminoindoles

Classical cannabinoids are those that can be extracted from plants or their synthetic analogues and include D9-tetrahydrocannabinol , D8-tetrahydrocannabinol, and 11 -hydroxy-D8 - tetrahydrocannabinol-dimethylheptyl (HU-210).

All of these are active at both CB1 and CB2 receptors although D9-tetrahydrocannabinol is a partial agonist at both receptors and in some CB2 receptor systems can be an antagonist. As might be expected from its close chemical homology, D8-tetrahydrocannabinol is also a partial agonist but its derivative HU-210 behaves as a full agonist relative to other potent, non-classical, agonists. HU-211 (also called dexanibol), stereoisomer of HU-210, is inactive at cannabinoid receptors. Thus, dexanibol is an antagonist at NMDA receptors and also inhibits production of tumour necrosis factor-a at a post-transcriptional stage; possibly for these reasons, it shows promise in the treatment of head injury.

The so-called ‘non-classical’ cannabinoids are characterised by being bi- or tri-cyclic compounds lacking the dihydropyran ring of the classical compounds. A commonly used agonist is CP55,940 which has high affinity and efficacy for both CB1 and CB2 receptors.

The alkylaminoindoles, of which WIN55,212-2 is the most commonly used, were derived from pravadoline, an inhibitor of cyclooxygenase which showed a pharmacological profile different from classical non-steroidal antiinflammatory agents.

WIN55,212-2, the R-(+) enantiomer, is active at both CB1 and CB2 receptors, though it shows some selectivity for the latter, whereas WIN55,212-3, the S-(x) enantiomer, is inactive. A recently synthesised analogue, JWH-015, shows some promise as a selective CB2 receptor agonist.

Per informazioni sui recettori
Per informazioni sui ligandi endogeni

Bibliography

C.ROBIN HILEY and WILLIAM R.FORD (2004) Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling
Biol.Rev., 79 pp 187-205

MANUEL GUZMAN. CRISTINA SANCHEZ, ISMAEL GALVE-ROPERH (2002) Cannabinoids and cell fate
Pharmacology & therapeutics 95 pp 175-184

Francesco Licciardi e Matteo Manfredi

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