In the mid-seventies, major efforts were focused on the identification of new natural cannabinoids isolated from preparations of Cannabis sativa and of other subspecies and varieties, such as Cannabis indica and Cannabis ruderalis. The two most abundant and most therapeutically relevant components of the plants are (–)-trans-Δ⁹–tetrahydrocannabinol (Δ⁹–THC) and (-)-cannabidiol (CBD) (Figure 1). Over these last two decades, the endocannabinoid system (ECS) related to the effects of Cannabis sativa has being emerging as target of pharmacotherapy showing very considerable physiological significance (Mechoulam et al., 2014). This system includes two cannabinoid receptors (CB₁ and CB₂) and endogenous ligands named endocannabinoids (Matsuda et al., 1990; Munro et al., 1993). CB₁ receptor is abundant in the brain, but to a less extend in peripheral tissues. CB₂ receptor is mainly expressed in immune cells.

Δ⁹–THC is responsible for the psychoactive effects of Cannabis sativa mediated by the activation of CB₁ receptor in the brain, whereas CBD is considered non-psychotropic. Currently, CBD is clinically used in association with Δ⁹–THC in a cannabis-based preparation (Sativex^®) that contains equimolar content of both for managing neuropathic symptoms associated with multiple sclerosis (Fernandez, 2016). CBD as a single drug is currently generating considerable interest due to its beneficial neuroprotective (Fernandez-Ruiz et al., 2013; Scuderi et al., 2014; Ibeas Bih et al., 2015), antiepileptic (Devinsky et al., 2015; Wright et al., 2015), hypoxia-ischemia (Lafuente et al., 2011; Mori et al., 2017), anxiolytic (Massi et al., 2013; Schier et al., 2014), antipsychotic (Bhattacharyya et al., 2010), analgesic (Maione et al., 2011), anti-inflammatory (Ruiz-Valdepeñas et al., 2011; Burstein, 2015), anti-asthmatic (Ribeiro et al., 2015; Vuolo et al., 2015), and antitumor properties (McAllister et al., 2011; Massi et al., 2013) among others(Mechoulam et al., 2007; Zhornitsky and Potvin, 2012; Renard et al., 2017; Watt and Karl, 2017). In 2016, GW pharmaceuticals reported the first positive results of CBD (Epidiolex^®) in phase III clinical trials for treatment-resistant seizure disorders, including Lennox–Gastaut and Dravet syndromes. An overview of regulatory approvals and clinical trials of CBD has been recently published (Fasinu et al., 2016).

The molecular targets involved in the diverse therapeutic properties produced by CBD are still not very well-understood (Morales et al., 2017). Unlike Δ⁹–THC, CBD does not bind to the orthosteric binding site of the CB₁ and CB₂ cannabinoid receptors (McPartland et al., 2007). Despite this lack of orthosteric affinity, CBD has been shown to antagonize the effects of the CB₁/CB₂ agonists CP–55,940 and WIN55212 at the mouse CB₁ and at the human CB₂ receptors (Pertwee et al., 2002; Thomas et al., 2007). Therefore, allosteric activity of CBD at these receptors has been hypothesized. In a recent report, CBD was shown to be a negative allosteric modulator of Δ⁹–THC and the endogenous cannabinoid 2–AG providing a possible explanation for some in vivo CBD effects (Laprairie et al., 2015; Morales et al., 2016). CBD has also been shown to modulate endocannabinoid tone by inhibiting the cellular uptake of the endocannabinoid anandamide (Leweke et al., 2012). This effect has been attributed to the fact that CBD competes with anandamide for binding to fatty acid-binding proteins (FABPs) which are intracellular proteins involved in the transport of anandamide to its metabolic enzyme fatty acid amide hydrolase (FAAH) (Elmes et al., 2015). Other possible molecular targets of CBD have been explored. Modulation of the GPR55 receptor by CBD has been evaluated in different signaling pathway assays. CBD acts as an antagonist preventing [³⁵S]GTPγS binding and Rho activation (Ryberg et al., 2007; Whyte et al., 2009; Ford et al., 2010), modulating Ca²⁺ mobilization (Lauckner et al., 2008) and β-arrestin recruitment (Yin et al., 2009). CBD has also been proposed as an antagonist of the GPR18 cannabinoid receptor (McHugh et al., 2012, 2014). Certain actions of CBD such as anti-inflammatory and immunosuppressive effects appear to be partially mediated through the serotonin and adenosine receptors that are not considered part of the ECS. For instance, CBD acts as a full 5-HT_1A agonist, 5-HT_2A weak partial agonist and a non-competitive 5HT_3A antagonist (Russo et al., 2005; Yang et al., 2010; Rock et al., 2012). The ability of CBD to activate the A_1A adenosine receptor has also been proposed (Gonca and Darıcı, 2014). Other molecular targets have also been studied, among them, the PPARγ nuclear receptors (O’Sullivan et al., 2009; Esposito et al., 2011; Scuderi et al., 2014), glycine receptors (Ahrens et al., 2009; Xiong et al., 2012), GABA_A receptors (Bakas et al., 2016), and transient receptor potential (TRP) channels (De Petrocellis et al., 2011, 2012). Studies focused on the possible epigenetic regulation of skin differentiation genes by CBD revealed that CBD is a transcriptional repressor that can control cell proliferation and differentiation through DNA methylation (Pucci et al., 2013). Despite all of this data, the mechanistic bases for the effects of CBD remain complex.

Cannabidiol constitutes one of the most important components of therapeutic interest from Cannabis sativa. However, unlike the numerous synthesized cannabimimetics generated to provide a synthetic alternative to THC, CBD derivatives have only been superficially explored. The purpose of this review is to provide a structural overlook at natural and synthetic CBD derivatives. Due to the fact that diverse molecular targets are involved in the therapeutic properties produced by CBD, we associated CBD structures to their biological targets. Thus, this review is intended to be a useful tool especially for medicinal chemists.

The basic structure of the CBD derivatives described in this review consists of 5-alkyl resorcinols substituted in position 2 by a propenylcyclohexene. Structural modifications on the alkyl side-chain, on the propenylcyclohexene, and substitution of the phenolic hydroxyl groups are concerned. Quinone CBD analogs are also included in this classification as far as their structures are closely related to CBD.

In a recently published review dedicated to the diversity of cannabis phytocannabinoids, the authors updated the inventory of naturally occurring CBD derivatives (Hanuš et al., 2016). Herein, we are associating these structures to their possible molecular targets.

Of the over 100 natural cannabinoids identified in Cannabis Sativa, seven have been classified as CBD-type compounds including CBD (Figure 2) (ElSohly and Slade, 2005; ElSohly and Gul, 2014; Aizpurua-Olaizola et al., 2016). All of them have the same absolute configuration than CBD; they are 5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-dioles retaining the trans-(1R,6R) configuration. Cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA-C3) are C3′-carboxylic derivatives, whereas cannabidiorcol (CBD-C1), cannabidiol-C4 also named as nor-cannabidiol (CBD-C4), and cannabidivarin (CBDV) differ from CBD by the length of their C4′-side chain. Cannabidiol monomethyl ether (CBDM), the C6′-methoxy CBD analog, was also isolated from the plant. Despite the potential therapeutic interest of these naturally occurring CBD derivatives, only a few related pharmacological studies have been reported (Table 1). Like most non-steroidal anti-inflammatory drugs, CBDA is characterized by a carboxylic group resulting in a selective inhibition of cyclooxygenase-2 (Takeda et al., 2008). CBDA does not have effect on anandamide inactivation in FAAH assays (Inhibition of [¹⁴C]-anandamide uptake: IC₅₀ > 50 μM) contrary to CBD (IC₅₀ = 28 μM) (Bisogno et al., 2001; Ligresti, 2006). Other molecular targets proposed for CBDA include GPR55 (Anavi-Goffer et al., 2012) and TRPA1 with moderate activity (De Petrocellis et al., 2011). CBDA has been shown to be an inhibitor of cell migration in the highly aggressive human breast cancer MDA-MB-231 by alteration of Rho GTPase activity (Takeda et al., 2012). CBDV, the C4′-propyl analog of CBD, displays very weak affinity for CB₁ and CB₂ receptors (Hill et al., 2013; Rosenthaler et al., 2014), whereas it has been reported to inhibit the activity of the putative endogenous ligand LPI in hGPR55-HEK293 cells (Anavi-Goffer et al., 2012). CBDV also targets the human TRPA1 channel (De Petrocellis et al., 2011, 2012). In several animal seizures models, CBDV exerted notable anticonvulsant effects without affecting normal motor function (Hill et al., 2012). The mechanisms through which CBDV exerts its antiepileptic effects are uncertain (Jones and Whalley, 2015). CBDV is currently in Phase II clinical trials as an antiepileptic drug under the name GWP42006.¹

Two aromatic analogs of CBD have been isolated from Lebanese hashish (ElSohly and Slade, 2005): cannabinodiol (CBND-C5), and cannabinodivarin (CBND-C3) (Figure 3) whose structural elucidation required their total synthesis (Robert et al., 1977). CBND-C₅ found in the plant’s flowers in low concentration, is considered a product of CBD photochemical conversion.

The conversion of CBD into human metabolites has been the subject of a recent interesting review (Ujváry and Hanuš, 2016). CBD biotransformation shows considerable species variability. The main biotransformation, including hydroxylation and oxidation, involves the CYP450 enzyme family. While 7-hydroxy-CBD (7-OH-CBD) derivatives are found in low concentration, the most abundant metabolites are hydroxylated 7-carboxylic acid derivatives of CBD (7-COOH-CBD, Figure 4). Glucuronidation of CBD seems to frequently occur at the phenolic oxygen (Figure 4). Another cannabinoid metabolite, the so called cannabielsoin (CBE), has been identified in plants as a product of photo-oxidation from CBD and CBDA (Shani and Mechoulam, 1974; Ujváry and Hanuš, 2016), or by biotransformation using tissue cultures under normal growth conditions (Hartsel et al., 1983; Yamamoto et al., 1991). CBE was also identified as a metabolite in guinea pigs, mice, rabbits, and rats (Yamamoto et al., 1991). Despite the fact that CBD metabolites have been the subject of many studies, few in vivo studies have been published. Therefore, their therapeutic benefits remain to be established.

Beyond the Cannabis plant, other naturally occuring products have been reported to interact with the ECS (Gertsch et al., 2010). However, only few of them are CBD-based compounds. Isolation and characterization of (+)-trans-hexahydrodibenzopyrans from the stem bark of the Amazonian liana Machaerium multiflorum Spruce led to the identification of the CBD related structures machaeridiols A, B, and C (Figure 5) (Muhammad et al., 2003). The total synthesis of these compounds via an efficient highly regio- and stereoselective approach has also been described (Huang et al., 2007). Although their activity at the CB₁ and CB₂ cannabinoid receptors has not been reported, these compounds displayed antimicrobial, antifungal, and antiparasitic activity in diverse in vitro assays (Muhammad et al., 2003). Machaeridiol B stands out as the most potent inhibitor against Plasmodium falciparum [chloroquine-sensitive (D6) and chloroquine-resistant (W2) clones] and Leishmania donovani with IC₅₀ values in the low micromolar range (Table 1).

Ferruginene C, a methylpentanol derivative of CBD (Figure 5), was recently isolated from the leaves of Rhododendron ferrugineum L. as a mixture of diastereoisomers (Seephonkai et al., 2011). Ferruginene C has been shown to be cytotoxic in the HL-60 cancer cell-line (IC₅₀ 13.7 μM) with selectivity toward non-cancerous cell-line. It binds weakly to CB₂ and TPRV1 receptors, but it did not show significant affinity for CB₁ and 5-HT_1A receptors (Table 1).

Even though linderatin (Figure 5), isolated from fresh leaves of Lindera umbellata Thunb. (Tanaka et al., 1984), is not considered a phytocannabinoid (Hanuš et al., 2016), it is interesting to include in the present review since closely related to CBD. No biological data have been reported so far.

Due to the promising therapeutic effects of CBD in a wide variety of diseases, synthetic CBD derivatives have attracted the attention of drug discovery programs in both industry and academia with the aim to improve the potency, efficacy, or pharmacokinetic properties of this interesting phytocannabinoid.

Synthetic approaches for different CBD metabolites such as 7-COOH-CBD or 7-OH-CBD (Figure 4) have been reported (Tchilibon and Mechoulam, 2000; Mechoulam and Hanuš, 2002). Moreover, structural modifications on different pharmacophoric positions such as the lipophilic side chain, the phenolic hydroxyl groups or the C7-methyl have been widely accomplished. In addition to the (-)-CBD enantiomers, the (+)-CBD derivatives [(+)-CBD depicted in Figure 6] have also been synthesized and pharmacologically evaluated (Bisogno et al., 2001; Fride et al., 2004; Hanus et al., 2005). Measurements of the binding affinities of these compounds for the CB₁ and CB₂ cannabinoid receptors yielded unexpected outcomes. Contrary to the naturally occurring (-)-CBD analogs, which showed no orthosteric affinity, most of the compounds in the (+)-CBD series bind to both receptors displaying selectivity toward CB₁ (Table 1).

Hydrogenation of CBD yielded the dihydro- and tetrahydro-cannabidiol derivatives H₂-CBD and H₄-CBD (Figure 6) (Ben-Shabat et al., 2006). Their effects on the production of reactive oxygen intermediates, nitric oxide, and tumor necrosis factor showed their anti-inflammatory capacity. In contrast to CBD, H₂-CBD, and H₄-CBD have affinity for the cannabinoid CB₁ 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. However, only the (+)-enantiomer (HU-465) displays affinity for the cannabinoid CB₁ and CB₂ receptors (Table 1).

A significant amount of preclinical data has shown the high therapeutic potential of CBD especially in inflammatory mouse models. According to ClinicalTrials.gov records, CBD is currently tested in clinical phases for different inflammatory diseases. The results of the first clinical study of CDB for the treatment of inflammatory bowel have been published very recently. Unfortunately, the effects of CBD on Crohn’s disease were ineffective in a randomized placebo-controlled trial on 20 patients probably due to low used doses (Naftali et al., 2017). The potential antiepileptic effects of CBD in patients suffering seizures associated with Lennox–Gastaut syndrome and in children and young patients with Dravet syndrome are currently on-going. The research has tended to focus on CBD therapeutic applications. Less attention has been paid to the therapeutic utility of CBD derivatives.

Despite the identifications of CBD metabolites and naturally occurring CBD analogs, in general, their pharmacological properties have not been extensively studies. In what concerns synthetic CBD-based compounds, several of them have shown interesting pharmacological properties but none has been introduced into clinical trials yet. In a pharmacological point of view, whereas CBD does not have affinity for both classical CB₁ and CB₂ cannabinoid receptors, most of (+)-CBD derivatives do bind to CB₁ and/or CB₂ receptors. Others, such as Abn-CBD, O-1602, CBG, cannabimovone, ferruginene C, (-)-CBDV, and (-)-CBDA, have shown activity at other receptors including TPRV1, GPR35 and/or GPR18 receptors, or enzymes such as COX-2. A limitation of the development of CBD synthetic derivatives probably resides in the lack of a unique common molecular target.

In future therapeutic development of CBD derivatives, it will be prudent to take into account some structural considerations around the CBD scaffold. One of them is the possible atropisomerism around the phenyl–hexenyl bond. Ortho-substitution on the phenyl ring could have stereochemical consequences generating hindered rotation of the phenyl–hexenyl bond due to steric or electronic constraints, generating two isolable conformers in the case of slow interconversion (Berber et al., 2014; Flos et al., 2016). Thus, it is necessary to consider the implication of a possible atropoisomerism for new CBD analogs discovery (Clayden et al., 2009).

The complexity of the pharmacological processes of CBD and CBD analogs suggest that a better understanding of their mechanism of action is required to devise successful synthetic CBD-based drug therapies.

PM, PHR, and NJ substantially contributed to the redaction of the manuscript. Then, they all approved the manuscript to be published.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.