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    Fungal Biotransformation of Cannabinoids PDF

    Uploaded by

    Diego Nicolas Mancera

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    © All Rights Reserved
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    REVIEW Curent pion nrg Discovery & Development 2009122150532 1 Thomson Reuters Sen LS SSH 2040337 Fungal biotransformations of cannabinoids: Potential for new effective drugs Sanjai Saxena Adress ‘Natural Products ana Orug Discovery Department of Blotechnelogy and Environmental Sclnces, ‘Thapar Unversity, Thapar Technology Campus, Patiala, Punjab 17004, nda Email ssarena@thapared Phytocannabinoids from the plant Cannabis sativa induce o variety of physiological and pharmacclogical responses in Iving systems, Including ant-infammator, antinociceptive, nt-ulcer and antitumor activites, The discovery of the cannabinoid receptars CB, and CB, led to the development of agonists and antagonists of these receptors for the treatment of a varlety of diseases. Nobilone, 0 synthetic erwative of 8°-ttrahydrocannabino!(S*-THC) which Is the main naturel psychotropic constituent of C sativa, was approved by the US FDA for the treatment of nausea and as an antiemetic for patients undergoing chemotherapy. 8?-THC and related cannabinoids are Involved In a. varety of signal transduction pathways: thus, reducing or removing the psychotropic effects of these compounds would fenhance their therapeutic spectra, Compound synthests and qualitative SAR studies are time-consuming activites; however, microbes ‘are effectively the most inventive synthetic chemists because of their metabolic pastcty. This review discusses the potential! of C sativa _mycoflora which is pathogenic as wel as endophytic, to remove the psychotrapic effects of A*-THC and related cannabinoids, and describes the development of « made system fr the ropid and cost-effective commercial production of cannabinoids through fermentation pothwors. Keywords 8?-THC, cannabinoid, drug dlscovery, endophytic fungi, fungal btragstormation Abbreviations CBD cennabidiol, THC tetrahydrocannabinel Introduction Biotransformation is the alteration of the structural and functional attributes of a parent chemical scaffold by biochemical pracesses within living systems. Enzymes play an inherent role in biotransformation, and variety ‘of chemical diversity is generated within living systems by exploiting the hydrolytic, _oxidation-reduction, condensation and \somerization capabilities of these enzymes. Biotransformation occurs in all living systems and refers to chemical changes or modifications performed by @ living organism on a chemical moiety or drug. This biological process Is more frequently referred to 9s biotransformation rather than drug metabolism (le, pharmacodynamics). The biotechnology developed for biotransformations is directed toward the production of molecules that have superior use as pharmacophores or as feedstock chemicals. for industry. Microbial biotransformations harness. the potential of fungal or bacterial systems to metabolize chemical molecules, thereby generating chemical diversity that could provide insight ta the possible metabolization ‘of drug molecules within humans. Furthermore, the use ‘of microbes as compared with mammalian medels of pharmacodynamics to study the breakdown of a single molecule is more efficient, because other xenobiotic compounds that are present in mammalian systems and may interact with the biotransformation under study are excluded. Cannabinoids: Potential source of pharmacophores Cannabis sativa is a plant that has long been exploited for recreational purposes because of Its psychoactive effects. The analgesic, appetite-stimulating, anti-emetic and anti-convulsant effects of C sativa were discovered by the British physician and surgeon William O'Shaughnessy in 41839 [1]. Phytochemical analysis revealed that C sativa contains @ variety of cannabinoids, some of which are responsible for the psychotropic activity of the plant [2]. Cannabinoids are terpenophenolic compounds that can be classified as phytocannabinolds (present in plant sources), endogenous cannabinoids or endocannabinoids (present in animal systems), and synthetic cannabinoids (chemically synthesized molecules). The development of the cannabinoid agonist research tool CP-55940 by Pfizer Inc marked the discovery of the cannabinoid receptor CB,, which potential target for drug discovery [3]. Marinol, Synhexyl and rabllone (Cesamet) are synthetic cannabinoid products that have been developed into pharmaceutical interventions, with use that varies based on the reguiatory compliance of individual countries [4] Phytocannabinoids Phytocannabinoids comprise approximately 60 closely related terpenophenolic compounds, including B-tetrehydrocannabinol (A*THC; Figure 1), _a-THC, tetrehydrocannabivarin (THCY), eannabigerol (CBG; the acid 1s showin in Figure 38), cannabichromene (CSC; 306 Cunet Opinion Drug Discover & Development 20092 No 2 Figure! The structure of -tetrahydrocannabinol. The green ring highlights the benzopyran ring with Cll) and EB) functional groups that are essential for bioactivity (this olety ts essential for CB, receptor recognition). The groups hightightea wath red tines inaicate ses of vansformation that coud possibly lead toa change in functionality. the acid is shown in Figure 3A), cannabidiol (CBD; the acid is shown in Figure 3A), cannabinol (CBN) and cannabichromene (CBC) [5,6]. The psychotropic nature of CBD and THC is unique because, unlike opiates, which also have psychotropic effects and are generally used in pain management, these compounds are devoid of nitrogen and are not alkaloids (7). Endocannabinoids : Endocannabinoids are produced in vivo in animal systems. The compounds were brought to the attention of researchers after the discovery of the cannabinoid receptors cB, and CB,. CB, receptors are expressed in the brain, peripheral nervous system, lungs, liver and kidneys. CB, receptors were first detected in spleen, and are expressed In T-cells, macrophages, B-cells of immune systems and hematopoietic cells [8]. The first endocannabinoid to be discovered was N-arachidonylethanolamine, also named anandamide (derived from the Sanskrit word for bliss and amide) [9]. Anandamide binds primarily to the CB, receptor and is present In a wide range of animals. ‘The pharmacology of anandamide is similar to that of THC, although anandamide has a different chemical structure ‘and a potency that is approximately half of that exhibited by THC [10]. To date, at least four further endocannabinoids have been identified: 2-erachidonylglycerol (2-AG) [11], 2-arachidonyigiycery! ether (aoladin ether) 12} O-arachidonylethanolamine (virodnamine) [13] and N-arachidony! dopamine (NADA) [14]. ‘Synthetic cannabinoids Synthetic cannabinoids are particularly useful in experiments to determine the SAR of cannabinoid compounds by making systematic, incremental modifications to the molecules. Synthetic cannabinoids include CP-55940 [15], HU-210 [16], SR-144528 [17], levonantradol [18] (Figure 2) and nabilone (Figure 2), which is used in cancer chemotherapy to overcome nausea and as an anti-emetic [19]. A°-Tetrahydrocannabinol: Scope of new drug development THC, the main psychoactive agent of C sativa, binds to the ‘CB, receptor, which Is distributed throughout the central ‘nervous system and at lower levels in some Figure 2. Compounds chemically derived from the pharmacophore of 4?-tetrahydrocannabinal. oak Eee So sttahycrocannbin! ay no on, 2 we on, sheen sid (cou Ptatmaeds) Peripheral tissues such as the liver and myocardium, More than 72 clinical trials performed by different research groups have demonstrated that THC and related cannabinoids have therapeutic potential as anti- ‘analgesics, anti-inflammatories, antispasties, antiemetics and apoptosis inducers, and for the alleviation of intra-ocular pressure in glaucoma and the prevention ‘of cerebral infarction, epilepsy and multiple sclerosis [20-25]. However, the use of cannabinoids, in particular A°-THC, Is responsible for side effects such as sleepiness, dizziness and confusion leading to the Impairment of memory, and cognitive and motor nerve functions. The development of new cannabinoid receptor agonists and antagonists based on a A’-THC template requires closer attention by medicinal chemists to obviate these side effects, Clinical trials based on SARs revealed that the benzopyran moiety of a?-THC does not confer activity, but is essential for biological activity (Figure 1). A variety of structural modifications were attempted, and derivatives such as levonantradol (Figure 2), L-hydroxysa*

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