*5.1. CB1*/*CB2 Receptors*

It has been shown that both the naturally occurring (−)-CBD enantiomer and its synthetic derivatives [(−)-7-hydroxy-5--dimethylheptyl-CBD, and (−)-1-COOH-5--dimethylheptyl-CBD] have weak a ffinity for the CB1 and CB2 cannabinoid receptors (Table 2). However, (+)-CBD and its derivatives [(+)-5--dimethylheptyl-CBD and (+)-7-hydroxy-5--dimethylheptyl-CBD] have high CB1 receptor a ffinity, slightly lower a ffinity for the CB2 receptor and inhibit AEA cellular uptake [120]. Similarly, (−)-7-hydroxy-dimethylheptyl-CBD can inhibit both AEA uptake and degradation through fatty acid amide hydrolase (FAAH) activity [121]. Recently, (−)-dimethylheptyl-CBD has been shown to be a CB1 receptor agonist (Table 2) in HEK-293A cells [122]. In addition, by reducing the expression of pro-inflammatory genes (IL-1b, IL-6, and TNFα), it exhibits a dose-dependent anti-inflammatory effect on microglia BV-2 cells [30].

Furthermore, hydrogenated CBD derivatives such as (+)-dihydrocannabidiol and (+)-tetrahydrocannabidiol have CB1 receptor a ffinity (Table 2) and show anti-inflammatory e ffects on the peritoneal cells of C57BL/6 mice and a macrophage cell line. This behavior may sugges<sup>t</sup> that the activation of pro-inflammatory mediators is not directly through the CB1 cannabinoid receptor [123]. Similarly, the (+)-8,9-dihydro-7-hydroxy-CBD derivative (HU-465), which has anti-inflammatory activity, especially at higher concentrations, binds to both CB1 and CB2 receptors, while its (−) enantiomer, (−)-8,9-dihydro-7-hydroxy-CBD (HU-446) has negligible a ffinity for both CB1 and CB2 receptors (Table 2). However, both HU-465 and HU-446 have been found to exhibit anti-inflammatory activity by inhibiting the release of IL-17 in mouse encephalitogenic T cells (TMOG) [124].

In addition, the pinene dimethoxy-dimethylheptyl-CBD derivative HU-308 [(3R, 4S, 6S)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol] and its enantiomer HU-433 [(3S, 4R, 6R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4- bicyclo[3.1.1]hept-3-enyl]methanol] were shown to have specific agonistic activity for the CB2 receptor (Table 2), and consequently, anti-inflammatory activity in cultured calvarial osteoblasts from C57BL/6J mice [125]. However, it has been found that HU-433 exhibits greater anti-inflammatory activity with poorer CB2 receptor binding affinity (Table 2) [125]. In contrast, HU-308, a CB2 agonist, was found to decrease TNF-α-induced expression of ICAM-1 and VCAM-1 in sinusoidal endothelial cells of human liver tissue [24]. Another CB2 receptor agonist, HU-910 ((1S,4R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-1-bicyclo[2.2.1]hept-2enyl]methanol)), significantly inhibits the effects of LPS that lead to increased inflammation (assessed by increased TNF-α expression) and increased oxidative stress (assessed by increased levels of 4-HNE and protein carbonyl groups) in mouse Kupffer cells [126]. This suggests that these effects are associated with CB2 receptor activation (Table 2).
