Antinociceptive effects of HUF-101, a fluorinated cannabidiol derivative

Abstract

Cannabidiol (CBD) is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. Here, we investigated whether HUF-101 (3, 10, and 30mg/kg), a fluorinated CBD analogue, would induce antinociceptive effects. HUF-101 effects were compared to those induced by CBD (10, 30, and 90mg/kg) and the cannabinoid CB_1/2 receptor agonist WIN55,212-2 (1, 3, and 5mg/kg). These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: hot plate, acetic acid-induced writhing, and carrageenan-induced inflammatory hyperalgesia. To evaluate the involvement of CB₁ and CB₂ receptors in HUF-101 and CBD effects, mice received the CB₁ receptor antagonist AM251 (1 or 3mg/kg) or the CB₂ receptor antagonist AM630 (1 or 3mg/kg) 30min before HUF-101, CBD, or WIN55,212-2. In the hot plate test, HUF-101 (30mg/kg) and WIN55,212-2 (5mg/kg) induced antinociceptive effects, which were attenuated by the pretreatment with AM251 and AM630. In the abdominal writhing test, CBD (30 and 90mg/kg), HUF-101 (30mg/kg), and WIN55,212-2 (3 and 5mg/kg) induced antinociceptive effects indicated by a reduction in the number of writhing. Whereas the pretreatment with AM630 did not mitigate the effects induced by any drug in this test, the pretreatment with AM251 attenuated the effect caused by WIN55,212-2. In the carrageenan-induced hyperalgesia test, CBD (30 and 90mg/kg), HUF-101 (3, 10 and 30mg/kg) and WIN55,212-2 (1mg/kg) decreased the intensity of mechanical hyperalgesia measured by the electronic von Frey method. The effects of all compounds were attenuated by the pretreatment with AM251 and AM630. Additionally, we evaluated whether HUF-101 would induce the classic cannabinoid CB₁ receptor-mediated tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception). Unlike WIN55,212-2, CBD and HUF-101 did not induce the cannabinoid tetrad. These findings show that HUF-101 produced antinociceptive effects at lower doses than CBD, indicating that the addition of fluoride improved its pharmacological profile. Furthermore, some of the antinociceptive effects of CBD and HUF-101 effects seem to involve the activation of CB₁ and CB₂ receptors.

Keywords: Cannabidiol; Cannabinoids; HUF-101; Nociception.