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. 2016 Jul 14;11(7):e0158779.
doi: 10.1371/journal.pone.0158779. eCollection 2016.

Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects

Aviva Breuer  1 , Christeene G Haj  1 , Manoela V Fogaça  2 , Felipe V Gomes  2 , Nicole Rodrigues Silva  2 , João Francisco Pedrazzi  3 , Elaine A Del Bel  4 , Jaime C Hallak  3 , José A Crippa  3 , Antonio W Zuardi  3 , Raphael Mechoulam  1 , Francisco S Guimarães  2
Affiliations

Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects

Aviva Breuer et al. PLoS One. .

Erratum in

Abstract

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 pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression 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 derivatives, 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 cannabinoid receptors.

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Conflict of interest statement

Competing Interests: The joint patent application submitted by Hebrew University and University of Sao Paulo authorities does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Reagents and conditions: (a) 1-fluoropyridinium triflate, CH2Cl2, r.t.
Fig 2
Fig 2. Reagents and conditions: (a) SeO2, t-BuOOH, CH2Cl2, r.t; (b) DAST, CH2Cl2, 0°C.
Fig 3
Fig 3. Reagents and conditions: (a) Pt(IV)oxide, H2, 10psi, EtOAc, r.t; (b) pyridine, acetic anhydride, r.t; (c) SeO2, EtOH, reflux; (d) NaBH4, EtOH, reflux; (e) DAST, CH2Cl2, -78°C–r.t.
Fig 4
Fig 4. Effect of 1 (1, 3 and 10 mg/kg, n = 6, 8 and 6 animals, respectively) in Swiss male mice tested in the forced swim test (FST, upper panel) and elevated plus maze (EPM).
Animals received an injection of vehicle (V, n = 7 animals/group) or 1 and were tested in the EPM 30min later. Immediately after the test they were submitted to the FST for 6 min. Data represents the means+SEM of immobility time in the FST and the % of open arm entries and time spent in these arms of the EPM. *indicates difference from V group (ANOVA followed by the Duncan test, p<0.05).
Fig 5
Fig 5. Effect of 3 (1, 3 and 10 mg/kg, n = 5, 5 and 6 animals, respectively) in Swiss male mice tested in the forced swim test (FST, upper panel) and elevated plus maze (EPM).
*indicates difference from V group (ANOVA followed by the Duncan test, p<0.05). Further specification as in Fig 4.
Fig 6
Fig 6. Effect of 5a (1, 3 and 10 mg/kg, n = 8–9 animals, respectively) in Swiss male mice tested in the forced swim test (FST, upper panel) and elevated plus maze (EPM).
*indicates difference from V group (ANOVA followed by the Duncan test, p<0.05). Further specification as in Fig 4.
Fig 7
Fig 7. Effect of 1 (1, 3 and 10 mg/kg, n = 7, 6 and 15 animals, respectively) in Swiss male mice tested in the pre-pulse inhibition model.
Animals received a first injection of vehicle (V) or 1 followed, 30 min later, by vehicle (n = 9) or amphetamine 10mg/kg (V+amphetamine group = 11 animals). *indicates difference from V+V group. + indicates difference from V+amphetamine group (ANOVA followed by the Duncan test, p<0.05).
Fig 8
Fig 8. Lack of effect of 2 (10, 30 and 60 mg/kg, n = 7–8 animals/group) in Swiss male mice tested in the pre-pulse inhibition model.
Animals received a first injection of vehicle (V) or 2 followed, 30 min later, by vehicle (n = 12) or amphetamine 10 mg/kg (V+amphetamine group = 11 animals). *indicates difference from V+V group (ANOVA followed by the Duncan test, p<0.05).
Fig 9
Fig 9. Lack of effect of 3 (10 and 30 mg/kg, n = 7–8 animals/group) in Swiss male mice tested in the pre-pulse inhibition model.
Animals received a first injection of vehicle (V) or 3 followed, 30 min later, by vehicle (n = 7) or amphetamine 10 mg/kg (V+amphetamine group = 7 animals). Data represents the means+SEM. *indicates difference from V+V group (ANOVA followed by the Duncan test, p<0.05).
Fig 10
Fig 10. Lack of effect of 5a (3, 10 and 30 mg/kg, n = 8 animals/group) in Swiss male mice tested in the pre-pulse inhibition model.
Animals received a first injection of vehicle (V) or 5a followed, 30 min later, by vehicle or amphetamine 10 mg/kg (V+amphetamine). *indicates difference from V+V group (ANOVA followed by the Duncan test, p<0.05). Further specifications as in Fig 7.
Fig 11
Fig 11. CBD (30–60 mg/kg, n = 10–11 animals/group), HUF-101 (10 mg/kg, n = 13–14 animals/group) and fluoxetine (10 mg/kg, n = 10 animals) decreased the number of buried marbles in the MBT test.
*indicates difference from V+V group (ANOVA followed by the Duncan test, p<0.05).
Fig 12
Fig 12. CBD (30 mg/kg, n = 7–9 animals/group) and HU-101 (10 mg/kg, n = 9–10 animals/group) decreased the number of buried marbles in the MBT.
This effect was prevented by pre-treatment with the CB1 (AM251 1 mg/kg, n = 9 animals/group) or CB2 (AM630, 1 mg/kg, n = 7 animals/group) receptor antagonist. *indicates difference from all other groups. +indicates difference from V+V group (ANOVA followed by the Duncan test, p<0.05).
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