*4.1. CB1*/*CB2 Receptors*

Cannabidiolic acid (CBDA), being a C3--carboxyl derivative of CBD (2,4-dihydroxy-3-[(1R, 6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-[alpha]-6-pentylbenzoic acid), acts as a selective COX2 and prostaglandin endoperoxide synthase inhibitor and exhibits anti-inflammatory properties in human breast cancer cells [113]. It has been suggested that its action may be due to a weak affinity for CB1 and CB2 receptors (Table 2) [114]. Similarly, other CBD derivatives, such as cannabidivarin (CBDV), which is a CBD analogue of C4--propyl (2-[(1R, 6R)-3-methyl-6-prop-1-en-2)-ylcyclohex-2-en-1-yl]-5-propylbenzene-1,3-diol), 7-hydroxy-CBD (7-OH-CBD) and the hydroxylated CBD derivative of 7-carboxylic acid (7-COOH-CBD) have poor affinities for CB1 and CB2 (Table 2) [2]. There is no published data examining their impact on the redox balance.

#### *4.2. GPR55 and TRPV1 Receptors*

CBDV has been found to have antagonistic effects on GPR55 (Table 2), which probably leads to anticonvulsant effects [115]. Therefore, this compound is suggested for use when therapeutic antiepileptic activities are needed. On the other hand, CBDA has been suggested to be an effective compound in analgesia and cancer through its agonistic action on TRPA1 and TRPV1 receptors (Table 2) and antagonistic action on TRPM8, similar to CBD [76,116].

Another natural phytocannabinoid is cannabimovone (1-[(1R, 2R, 3R, 4R)-3-(2,6-dihydroxy-4-pentylphenyl)-2-hydroxy-4-prop-1-en-2-ylcyclopentyl] ethanone), which has low a ffinity for the CB1 and CB2 receptors, but significant a ffinity for TRPV1 (Table 2) [117].

In contrast, cannabigivarin (a cannabigerol ropyl analogue) has been shown to stimulate and desensitize human TRPV1 (Table 2) [72]. It is also known that TRPV1 receptor activity is deeply involved in oxidative stress and inflammation [114]. Based on the understanding of the relationship between TRPV1 and oxidative stress described in Section 3.5, all of these derivatives may provide di fferent therapeutic approaches in the case of inflammation and oxidative stress.

#### *4.3. 5-HT1A and PPAR*γ *Receptors*

It has been shown that another CBD derivative, cannabigerol (CBG; (2-[(2E)-3,7-dimethylocta-2, 6-dienyl]-5-pentylbenzene-1,3-diol]), a naturally open analogue of cyclohexenyl CBD, activates TRPV1 as well as 5-HT1A (Table 2) and has antidepressant and anti-inflammatory e ffects in intestinal diseases [2,72,118]. CBG may also bind to PPARγ (Table 2) and increase its transcriptional activity [92]. Studies on the HEK293 cell line have shown that CBG, by activating PPARγ, significantly reduces the secretion of inflammatory mediators such as IL-6 and TNFα [119].

#### **5. E** ff**ects of Synthetic Derivatives of CBD on Receptors**

Given the limitations in the biological activity of CBD itself and its natural derivatives and the fact that the biological properties of CBD derivatives depend on their structure, synthetic derivatives are produced that have been designed so that their structure allows direct interaction with components of the redox system or indirectly with molecular targets interacting with these components, including the cannabinoid receptors (Table 2). The derivatives with potential antioxidant and anti-inflammatory e ffects include, but are not limited to, (+)-CBD derivatives, dihydrocannabidiol and tetrahydrocannabidiol derivatives, and (+)-dihydro-7-hydroxy-CBD [2]. Promising synthetic derivatives that can modulate redox balance and/or inflammation are presented below.
