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Cannabidiol (CBD) and Its Analogs: a Review of Their Effects on Inflammation

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Cannabidiol (CBD) and Its Analogs: a Review of Their Effects on Inflammation Bioorganic & Medicinal Chemistry xxx (2015) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Review Cannabidiol (CBD) and its analogs: a review of their effects on inflammation ⇑ Sumner Burstein Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605, United States article info abstract Article history: First isolated from Cannabis in 1940 by Roger Adams, the structure of CBD was not completely elucidated Received 24 December 2014 until 1963. Subsequent studies resulted in the pronouncement that THC was the ‘active’ principle of Revised 23 January 2015 Cannabis and research then focused primarily on it to the virtual exclusion of CBD. This was no doubt Accepted 30 January 2015 due to the belief that activity meant psychoactivity that was shown by THC and not by CBD. In retrospect Available online xxxx this must be seen as unfortunate since a number of actions of CBD with potential therapeutic benefit were downplayed for many years. In this review, attention will be focused on the effects of CBD in the Keywords: broad area of inflammation where such benefits seem likely to be developed. Topics covered in this Cannabidiol review are; the medicinal chemistry of CBD, CBD receptor binding involved in controlling Inflammation, D9-Tetrahydrocannabinol Anti-inflammatory signaling events generated by CBD, downstream events affected by CBD (gene expression and transcrip- CBD receptor binding tion), functional effects reported for CBD and combined THC plus CBD treatment. Signaling events Ó 2015 Elsevier Ltd. All rights reserved. Downstream events Functional effects Contents 1. Introduction . ....................................................................................................... 00 2. Medicinal chemistry of CBD . .................................................................................... 00 2.1. Conformation. .......................................................................................... 00 2.2. Natural homologs and synthetic analogs. .......................................................................... 00 3. Receptor binding involved in controlling inflammation . ................................................................. 00 3.1. CB1 cannabinoid receptor.......................................................................................... 00 3.2. CB2 cannabinoid receptor.......................................................................................... 00 3.3. Adenosine A2A receptors .......................................................................................... 00 3.4. CB2/5HT(1A) heterodimerization . .......................................................................... 00 3.5. TRPV1 receptor . .......................................................................................... 00 3.6. GPR55 Receptor . .......................................................................................... 00 4. Signaling events generated by CBD. .................................................................................... 00 4.1. Eicosanoids . .......................................................................................... 00 4.1.1. Arachidonic acid release. ............................................................................... 00 4.1.2. Cyclooxygenase and products ............................................................................... 00 4.1.3. Lipid storage diseases. ............................................................................... 00 Abbreviations: CBD, cannabidiol; CBCy, cannabicyclol; CBCR, cannabichromene; CBGA, cannabigerolic acid; CBGV, cannabigerovarin; CBN, cannabinol; CBG, cannabigerol; DMH, dimethylheptyl; LPS, lipopolysaccharide; NBMPR, S-(4-ni- trobenzyl)-6-thioinosine; NFAT, nuclear factor of activated T-cells; PLA2, phospho- 9 lipase A2; THC, D -tetrahydrocannabinol; THCV, tetrahydrocannabivarin; TNF-a, tumor necrosis factor-a; ROI, reactive oxygen intermediates; NAgly, N-arachidonoyl glycine; CIA, collagen-induced arthritis; FAAH, fatty acid amide hydrolase; OPC, oligodendrocyte progenitor cells. ⇑ Tel.: +1 508 856 2850; fax: +1 508 856 2003. E-mail address: [email protected] http://dx.doi.org/10.1016/j.bmc.2015.01.059 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Burstein, S. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.01.059 2 S. Burstein / Bioorg. Med. Chem. xxx (2015) xxx–xxx 4.2. Cytokines . ................................................................................................ 00 4.3. Effects of CBD on intracellular Ca++ levels . ............................................................. 00 5. Downstream events affected by CBD: gene expression and transcription . .................................................... 00 5.1. Comparative microarray analysis . ............................................................................. 00 5.2. Expression of glial fibrillary acidic protein mRNA . ............................................................. 00 5.3. PPARc involvement. ............................................................................. 00 5.4. Production of reactive oxygen intermediates . ............................................................. 00 6. Functional effects reported for CBD . ....................................................................... 00 6.1. Anti-arthritic effect in CIA . ............................................................................. 00 6.2. Anti-inflammatory clinical effects of HU-320 (Fig. 2)................................................................... 00 6.3. Edema and hyperalgesia . ............................................................................. 00 6.4. Arachidonic acid-induced ear inflammation . ............................................................. 00 6.5. Inflammatory bowel disease. ............................................................................. 00 6.6. Chemically induced colitis . ............................................................................. 00 6.7. Human neutrophil migration . ............................................................................. 00 6.8. Type I diabetic cardiomyopathy . ............................................................................. 00 6.9. Elevation of cytokine production . ............................................................................. 00 6.10. Pneumococcal meningitis . ............................................................................. 00 6.11. Treatment of demyelinating pathologies ............................................................................. 00 6.12. Hepatic ischemia-reperfusion injury . ............................................................................. 00 6.13. Sepsis-related encephalitis . ............................................................................. 00 6.14. Autoimmune encephalomyelitis. ............................................................................. 00 6.15. Inflammatory lung diseases . ............................................................................. 00 7. Combined THC and CBD treatment. ....................................................................... 00 8. Summary . .......................................................................................................... 00 Acknowledgement. .............................................................................................. 00 References and notes . .............................................................................................. 00 1. Introduction Recent years have seen a dramatic increase in interest in the major phytocannabinoid, cannabidiol. For the period 2008 to the present, 1205 publications can be found in a PubMed search using the keyword cannabidiol. This compares with lists of 225 reports for the years 2003–2007 and 50 for 1999–2002.1 First isolated from Cannabis in 1940,2 the structure shown in Figure 1 was not report- ed until 1963.3 Subsequent studies on Cannabis resulted in the pro- nouncement that THC was the ‘active’ principle and research then focused primarily on it to the virtual exclusion of CBD. This was no doubt due to the belief that activity meant psychoactivity that was shown by THC and not by CBD. In retrospect, this must be seen as unfortunate since a number of actions of CBD with potential therapeutic benefit were overlooked for many years. In this review, attention will be focused on the effects of CBD on the broad area of inflammation where such benefits seem likely to be realized. CBD THC 2. Medicinal chemistry of CBD A 2.1. Conformation Although there is considerable structural overlap between CBD and THC (Fig. 1), the conformational structures shown in Figure 1A differ significantly.4 Whereas THC exists in an essentially planar conformation, CBD adopts a conformation in which the two rings are more or less at right angles to each other (Fig. 1). A result of this is the observation that CBD does not bind to or activate the CB1 receptor an action that THC is capable of doing. This in turn leads B to a complete lack of psychoactivity by CBD unlike THC, which is the psychoactive principle of Cannabis. The basis of this is a so- Figure 1. The minimal energy conformations of CBD and D9-tetrahydrocannabinol called ‘region of steric interference’5 on the CB1 receptor that (THC) are shown
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