*3.8. 5-HT1A Receptor*

CBD has direct affinity for the human 5-HT1A (serotonin) receptor [101]. In addition, CBD can induce the 5-HT1A receptor indirectly by increasing the level of AEA [102]. However, the activated 5-HT1A receptor can act as a membrane antioxidant by capturing ROS [103]. Therefore, through activation of 5-HT1A, CBD can counteract peroxidation of phospholipids and thus participate in the protection of biomembranes against oxidative modifications. In addition, studies in Wistar rats have shown that CBD, by activating 5-HT1A receptors, can reduce physiological and behavioral responses to restrictive stress [104]. CBD has also been suggested as a therapeutic compound for the treatment of painful diabetic neuropathy due to its ability to activate 5-HT1A receptors [10].

#### *3.9. Adenosine A2A Receptors*

CBD is also an agonist of adenosine A2A receptors [61], which are G-protein coupled receptors. They are expressed in various cell types, participate in numerous physiological and pathological processes and also regulate inflammatory processes [105]. Adenosine and its agonists exhibit anti-inflammatory activity in vivo [106]. Therefore, adenosine release is one of the mechanisms of immunosuppression during inflammation [107], and adenosine receptor agonists reduce TNF-α levels [108,109]. It has been shown that CBD by activating A2A adenosine receptors can reduce the level of vascular cell adhesion molecule (VCAM-1) in endothelial cells in SJL/J mice, which may provide a new mechanism to control neuroinflammatory diseases such as multiple sclerosis (MS) [110].

In addition, it has been found that A2A activation can prevent reperfusion consequences and alleviate oxidative stress in mitochondria [111]. This suggests that CBD prevents oxidative stress by activating A2A receptors. It was also shown that A2A receptors can form heteromers with CB1 receptors in CA1 neurons and in the hippocampus of C57BL/6J mice [112]. Therefore, CBD can modify the functioning of the entire heteromer, and thus modulate the activation of two groups of receptors involved in the regulation of redox balance and inflammation.

**Figure 4.** Major effects of CBD on several membrane receptors (AEA, anandamide; 2-AG, 2-arachidonoylglycerol; FAAH, fatty acid amide hydrolase; AMT, AEA membrane transporter; ROS, reactive oxygen species; Ub, ubiquitin; p65, transcription factor NF-κB; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response elements. Blue arrows indicate agonist activity; red arrows indicate antagonist activity; dashed blue arrows indicate weakly agonistic activity; green arrows indicate endocannabinoid agonist activity; grey arrows indicate chemical and biological effects).

#### **4. E**ff**ects of Natural Derivatives of CBD on Receptors**

Due to the range of CBD metabolic effects known to date, interest in the possibility of using this phytocannabinoid is constantly growing. Considering the fact that modifications to the CBD structure may result in an improved therapeutic profile and biological activity, natural CBD derivatives are sought and their therapeutic utility is being evaluated. Therefore, known or potential effects of naturally occurring CBD derivatives are presented. Their activity through membrane receptors is emphasized, which are described in this review as those which under the influence of CBD show antioxidant and/or anti-inflammatory activities.
