<scp>HU</scp>‐446 and <scp>HU</scp>‐465, Derivatives of the Non‐psychoactive Cannabinoid Cannabidiol, Decrease the Activation of Encephalitogenic T Cells

Kozela, Ewa; Haj, Christeene; Hanŭs, L; Chourasia, Mukesh; Shurki, Avital; Juknat, Ana; Kaushansky, Nathali; Mechoulam, Raphael; Vogel, Zvi

doi:10.1111/cbdd.12637

Cited by 30 publications

(26 citation statements)

References 51 publications

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“…Similarly, the (+)-8,9-dihydro-7-hydroxy-CBD derivative (HU-465), which has anti-inflammatory activity, especially at higher concentrations, binds to both CB1 and CB2 receptors, while its (−) enantiomer, (−)-8,9-dihydro-7-hydroxy-CBD (HU-446) has negligible affinity for both CB1 and CB2 receptors ( Table 2). However, both HU-465 and HU-446 have been found to exhibit anti-inflammatory activity by inhibiting the release of IL-17 in mouse encephalitogenic T cells (TMOG) [124].…”

Section: Cb1/cb2 Receptorsmentioning

confidence: 99%

“…Table 2. Influence of natural and synthetic CBD derivatives on receptor activation (X: agonist activation or Y: antagonist activation by related CBD derivative; * weak affinity; #: full name is in chapter 4.1) [2,24,72,76,[114][115][116]120,[122][123][124][125][126][127]130]. Natural CB1 CB2 Gpr55 Gpr18 TRPV1 TRPA1 TRPM8 5-HT…”

Section: Trpv1 5-ht 1a and Adenosine A 2a Receptorsmentioning

confidence: 99%

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Antioxidative and Anti-Inflammatory Properties of Cannabidiol

2019

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Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.Antioxidants 2020, 9, 21 2 of 20 Moreover, this phytocannabinoid accelerated wound healing in a diabetic rat model by protecting the endothelial growth factor (VEGF) [11]. In addition, by preventing the formation of oxidative stress in the retina neurons of diabetic animals, CBD counteracted tyrosine nitration, which can lead to glutamate accumulation and neuronal cell death [12].This review summarizes the chemical and biological effects of CBD and its natural and synthetic derivatives. Particular attention was paid to the antioxidant and anti-inflammatory effects of CBD and its derivatives, bearing in mind the possibilities of using this phytocannabinoid to protect against oxidative stress and the consequences associated with oxidative modifications of proteins and lipids. Although CBD demonstrates safety and a good side effect profile in many clinical trials [4], all of the therapeutic options for CBD discussed in this review are limited in a concentration-dependent manner. Molecular Structure of CBDCBD is a terpenophenol compound containing twenty-one carbon atoms, with the formula C 21 H 30 O 2 and a molecular weight of 314.464 g/mol (Figure 1). The chemical structure of cannabidiol, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1, 3-benzenediol, was determined in 1963 [13]. The current IUPAC preferred terminology is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. Naturally occurring CBD has a (−)-CBD structure [14]. The CBD molecule contains a cyclohexene ring (A), a phenolic ring (B) and a pentyl side chain. In addition, the terpenic ring (A) and the aromatic ring (B) are located in planes that are almost perpendicular to each other [15]. There are four known CBD side chain homologs, which are methyl, n-propyl, n-butyl, and n-pentyl [16]. All known CBD forms (Table 1) have absolute trans configuration in positions 1R and 6R [16].

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Section: Cb1/cb2 Receptorsmentioning

confidence: 99%

Section: Trpv1 5-ht 1a and Adenosine A 2a Receptorsmentioning

confidence: 99%

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

2019

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“…The synthesis of HU-444 is presented in Scheme 1. The synthetic steps a, b, and c are published in Kozela et al (2015). Below we describe in detail the subsequent reaction steps d-i.…”

Section: Methodsmentioning

confidence: 99%

HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

Haj

Sumariwalla

Hanŭs

et al. 2015

J Pharmacol Exp Ther

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Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to D 9 -tetrahydrocannabinol (D 9 -THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-a, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive D 9 -THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a D 9-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-a and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause D 9-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

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“…In contrast to CBD, H 2 -CBD, and H 4 -CBD have affinity for the cannabinoid CB 1 receptor ( Table 1 ). Additionally, the (-)- and (+)-dihydro-7-hydroxy-CBD enantiomers (HU-446 and HU-465, Figure 6 ) have recently been synthesized and biologically characterized in an inflammatory model of encephalitogenic T cells (Kozela et al, 2015). Both compounds showed anti-inflammatory potential in inflammatory and autoimmune diseases models.…”

Section: Synthetic Cbd Analogsmentioning

confidence: 99%

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol

2017

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Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.

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HU‐446 and HU‐465, Derivatives of the Non‐psychoactive Cannabinoid Cannabidiol, Decrease the Activation of Encephalitogenic T Cells

Cited by 30 publications

References 51 publications

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol

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