*5.2. GPR Receptors*

Abnormal CBD (4-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol), named O-1602, is a synthetic CBD regioisomer and a selective GPR55 receptor agonist (Table 2), but not a CB1/CB2 receptor agonist. It causes vasodilation independent of the receptors as well [2,127]. Therefore, it has been suggested that O-1602 can be used to regulate ROS/RNS levels and modify the effect of oxidative stress on cellular metabolism by modulating GPR55 receptor activation [58]. In addition, O-1602, as a GPR18 agonist, mediates the reduction of cyclic adenosine monophosphate (cAMP) and the activation of the PI3K/AKT and ERK1/2 pathways in vitro [128]. A Sprague-Dawley rat study showed that GPR18 receptor activation via O-1602 leads to reduction of ROS levels, however inhibition of GPR18 receptor activation increases oxidative stress by increasing ROS production [129].

#### *5.3. PPAR* γ *Receptor*

Recently it has also been found that the synthetic quinoline derivatives of CBG, VCE-003 [(2-[(2E)-3,7-dimethylocta-2,6-dienyl]-3-hydroxy-5-pentylcyclohexa-2,5-dien-1,4-dione)] and HU-331 [(3-hydroxy-2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylcyclohexa-2,5-dien-1, 4-dione], activate the PPARγ receptor as CBG does (Table 2) [130]. HU-311 was shown to interfere with mitochondrial transmembrane potential and induce ROS generation, as well as activate the Nrf2 pathway [130]. However, another CBD derivative, VCE-003, induces PPARγ-mediated antioxidant and anti-inflammatory activity that prevents neuronal damage caused by inflammation in the Parkinson's mouse model (intravascular LPS injection). The same effect was seen in the in vitro cellular model of neurological inflammation (BV2 cells exposed to LPS and M-213 cells treated with media prepared from BV2 cells exposed to LPS) [131].

#### *5.4. TRPV1, 5-HT1A and Adenosine A2A Receptors*

Despite extensive research into the biological effects of synthetic CBD derivatives, they have not been evaluated for their interaction with TRPV1, 5-HT1A and adenosine A2A receptors in the context of anti-inflammatory and antioxidant activity.


