Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects
Aviva Breuer, Christeene G. Haj, Manoela V. Fogaça, Felipe V. Gomes, Nicole Rodrigues Silva, João Francisco Pedrazzi, Elaine A. Del Bel, Jaime C. Hallak, José A. Crippa, Antonio W. Zuardi, Raphael Mechoulam, Francisco S. Guimarães
PLOS One, 2016, 11, (7), e0158779, 1-19.
Doi : 10.1371/journal.pone.0158779
Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharma- cological assays, including mice tests for anxiety, obsessive-compulsive disorder, depres- sion and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD deriv- atives, one of which, 4′-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti- compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on can- nabinoid receptors.
Cannabidiol (CBD) is a major cannabinoid present in Cannabis sativa, which does not cause the typical effects of the psychoactive component, Δ9-tetrahydrocannabinol (THC). CBD was isolated from marijuana in 1940 by Adams et al  in the US and from Egyptian hashish by Jacob and Todd  in the UK. Its structure was elucidated in 1963  and its absolute configu- ration was established in 1967 .
Numerous preclinical studies indicate that CBD exerts therapeutic effects in animal models of a wide range of health disorders, including neuropsychiatric conditions. Several mechanisms have been suggested to be involved in the actions of CBD: activation of TRPV1 channels, inhi- bition of uptake and metabolism of the endocannabinoid anandamide, inhibition of adenosine uptake, GPR55 antagonism, PPARγ and 5-HT1A receptors agonism, intracellular Ca++ increase, anti-oxidative effects etc. For reviews see [5–9]. More recently, a direct interaction with the mTOR/p70S6 kinase signaling has been proposed as a possible mechanism of CBD antipsychotic effects .
CBD was initially reported in 1980 to be anti-epileptic in a small trial of adult patients  and today plant extracts with high levels of CBD are widely administered to epileptic children. Positive results of larger clinical pediatric studies have already been published [12,13] and the drug has recently received orphan designation by regulatory agencies .
In the psychiatry field the initial findings that CBD attenuates the psychotomimetic and anxiogenic effects induced by high doses of THC in humans led to the assumption that this drug could possess antipsychotic and anxiolityc properties . CBD indeed decreases behav- ioral changes induced in rodents by dopamine agonists or glutamate NMDA receptor antago- nists [16–19]. Anxiolytic-like effects of CBD in rodents have also been described in different animal models after either acute or repeated administration [20–22]. CBD, at single doses of 300–600 mg/day, was also shown to attenuate public speaking-induced anxiety in healthy sub- jects and patients with social anxiety .
Extending these findings, we recently reported that CBD could also induce antidepressant- and anticompulsive-like effects in rodents tested in the forced swimming test and marble bury- ing tests, respectively [24, 25].
Clinical antipsychotic effects of CBD (with doses reaching above 1 g/day) were initially described in open-label studies by Zuardi et al [26,27]. and have been recently confirmed (again, with doses of 800 mg/day) by Leweke et al. in a randomized, double blind clinical trial .
It is somewhat surprising that in spite of the very promising pharmacological/clinical effects of CBD and its lack of toxicity it has not been developed as a single drug. CBD is marketed together with Δ9-THC (in a 1:1 ratio) by GW Pharmaceuticals as Sativex, sold in Canada and several European countries for spasticity, due to multiple sclerosis . One of the reasons may be the very high doses needed for activity in humans (see above). Therefore, the develop- ment of more potent CBD-type compounds is desirable.
The activity of numerous endogenous constituents and synthetic drugs has been enhanced by the introduction of a fluorine atom in their molecules [30,31]. Indeed, nearly 20% of new drugs reaching the pharmaceutical market contain a fluorine atom . Many of these are lipo- philic molecules such as steroids and fatty acid derivatives. The phytocannabinoids, including CBD, are likewise lipophilic. Hence we decided to fluorinate CBD at various positions and eval- uate the activity of the novel molecules.
We report now the synthesis of 3 fluorinated CBD derivatives—one with the fluorine on the aromatic ring (HUF-101) (1), a second one with fluorine on the propylidene moiety of CBD diacetate (HUF-102) (2) and a third one with fluorine on the C-7 methyl group of the terpene ring of 8,9- dihydro-CBD (HUF-103) (3). We report the effects of these new molecules in rodent models predictive of anxiolytic, antidepressant, antipsychotic and anticompulsive effects.