Pharmacological and Therapeutic Secrets of Plant and Brain (Endo)Cannabinoids
Shared by Susan Rutherford
Lumı´r Ondrˇej Hanusˇ Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, Hebrew University, Ein Kerem Campus, Jerusalem 91120, Israel
Published online 5 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.20135 !
Research on the chemistry and pharmacology of cannabinoids and endocannabinoids has reached enormous proportions, with approximately 15,000 articles on Cannabis sativa L. and cannabinoids and over 2,000 articles on endocannabinoids. The present review deals with the history of the Cannabis sativa L. plant, its uses, constituent compounds and their biogeneses, and similarity to compounds from Radula spp. In addition, details of the pharmacology of natural cannabinoids, as well as synthetic agonists and antagonists are presented. Finally, details regarding the pioneering isolation of the endocannabinoid anandamide, as well as the pharmacology and potential therapeutic uses of endocannabinoid congeners are presented. 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 2, 213–271, 2009 Key words: cannabis; cannabinoids; endocannabinoids; pharmacology; receptors 1.
Cannabis sativa L. (hemp) and its phytochemical products (hashish, marihuana) are the most widely produced, plant-based, illicit drugs and the illegal drug most frequently used in Europe. The illegal status and widespread use of Cannabis has simultaneously stimulated efforts to identify the psychoactive constituents of Cannabis while making basic and clinical research on the properties of Cannabis difficult. Despite these obstacles, the discovery of endocannabinoids and delineation of their biochemical and physiological actions in multiple organ systems is currently a significant arena of research. Similarly, the medicinal properties of Cannabis products have been recognized for millennia, but their legal or licensed use in medicine remains controversial. The most prominent therapeutic indications for Cannabis-derived galenicals, or related products (e.g., Marinol) in the modern world include: as an analgesic for cancer pain, post-operative pain, and phantom limb pain; Correspondence to: Dr. Lum|¤r Ondrej Hanus, Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine,Hebrew University,Ein Kerem Campus, Jerusalem 91120, Israel.E-mail: email@example.com Medicinal Research Reviews, Vol. 29, No. 2, 213 ^271, 2009 2008 Wiley Periodicals, Inc. for decreasing intraocular pressure in glaucoma; reducing spasticity, ataxia, and muscle weakness associated with multiple sclerosis, cerebral palsy, and spinal cord injuries; bronchodilatation in asthma, suppressing emesis induced by oncolytics; and appetite stimulation in response to cachexia/ anorexia caused by opioids, antivirals, AIDS-related illnesses or terminal cancer. With active research describing the wide variety of the endocannabinoid system and its receptors currently ongoing, additional medicinal applications for the use of synthetic cannabinoid ligands of greater selectivity and reduced side-effect profile than the galenicals will undoubtedly arise in the future. The first medicinal applications of plant-derived cannabinoids are lost to time. Nonetheless, they provided the impetus for determining the receptors in the body that mediated their effects, and raised the possibility of endogenous ligands for those receptors. The first steps towards identifying these endocannabinoids, broadening the potential for new therapeutic modalities, began on March 24, 1992. Exactly 555 days after numerous extractions of porcine brains, followed by additional isolations and purifications, this analytical chemist held in his hands a fraction containing the first identified endogenous ligand for the central cannabinoid receptor, N-arachidonoylethanolamine, later named anandamide. Thin-layer chromatography revealed that this preparation contained only one compound, and gas chromatography indicated it had one tailing peak, which converted to a sharp, symmetrical peak after silylation. The molecular pharmacologist William Devane established the screening assay, using the central cannabinoid (CB1) receptor, for pharmacologically identifying the compound. The day after isolating the compound to be named anandamide, its affinity (Ki) for the CB1 receptor was determined to be 39.0 5.0 nM. In this system, the Ki of D9 -THC, one of the psychoactive components of Cannabis, was determined to be 46.0 3.0 nM. On May 13, 2002, spectrometrist Asher Gopher measured the mass spectrum of the un-derivatized material and determined the molecular weight of the parent ion to be 329 (Fig. 5A). The following day, the molecular weight of the silylated compound was found to be 419, a difference of 18 resulting from the dehydration of the sample during analysis (Fig. 5B). Subsequently, we started to solve the structure of this compound and on July 13, the structure was determined by Raphel Mechoulam to be N-arachidonoylethanolamine, who named it anadamide, from the Sanskrit for ‘‘eternal bliss.’’ Aviva Breuer synthesized this compound on August 20, 1992, and the spectra of the natural and synthetic compounds were compared, verifying the structural identification. The isolation and identification of the first endogenous cannabinoid was an important milestone in the field of cannabinoid pharmacology. The way to this point was very long and started more than 100 years ago. A summary of the work that came before and after the identification of anandamide is the subject of this review.
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