As members of G-protein-coupled receptors (GPCRs) family, cannabinoid receptors (CBRs) have been extensively studied due to their crucial role in a wide range of central and peripheral disorders [1]. CBRs can be categorized into cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R) based on their different distribution in the human body. Like other GPCRs, both CB1R and CB2R possess seven transmembrane regions [2]. Of note, CB1R shares a high degree of homology with CB2R [3], with 44 % sequence identity across their entire sequences and 68 % identity across their membrane regions [4]. CB1R is predominantly found in the central nerve system (CNS), while CB2R is mainly distributed in the periphery, including the cardiovascular, skeletal, gastrointestinal and skin systems (Fig. 1) [5]. As for CB1R, it can be activated by tetrahydrocannabinol (THC), an extract of cannabis sativa, leading to induce the disordered mental and physiological responses, which are the primary drivers of addiction [6]. Besides, CB1R has been confirmed to be closely associated with neurodegenerative disease, like Parkinson's disease (PD) [7] and Alzheimer's disease (AD) [8]. Recently, CB1R has emerged as a potential drug target for the treatment of pain [9], anti-anxiety therapy [10], anti-convulsive treatment [11], gout management [12] and obesity [13]. Nevertheless, active compounds targeting CB1R often result in psychiatric side effects, like enhanced anxiety, depression, and even suicide risk [14]. These inevitable neurological side effect give rise to a significant hurdle in the development of drugs targeting CB1R [15]. In comparison, CB2R is rarely found in the CNS, and is primarily located within the immune system to mediate corresponding immune diseases, including neuroinflammation [16], lysosomal disease [17] and rheumatoid arthritis [18]. Due to the substantial neurological side effects associated with CB1R activation, CB2R has gained attention as an ideal druggable target for the treatment of related diseases [15].

In 1993, CB2R was cloned using polymerase chain reaction (PCR) in human promyelocytic leukaemic cells (HL60) [19]. Like other GPCRs, CB2R consists of seven transmembrane helices that bind with intracellular and extracellular loop containing the N-terminus [20]. It is worth noting that human CB2R shares a high sequence homology with those of mice and rats [21]. In humans, CB2R is involved in a number of physiological activities, and its abnormal expression can induce a possible pathology [22], [23]. For instance, CB2R is implicated in energy metabolism process, and the deletion of CB2R gene could result in obesity and disruption of physiological activities [24], [25]. Conversely, overexpression of the CB2R could lead to hyperglycemia in mice [26]. These significant physiological actions of CB2R make it be a viable target for the treatment of corresponding disorders [27].

As shown in Fig. 2, GPCRs are involved in the activation of multiple signaling pathways, and interact with different proteins (Gα and Gβγ). Importantly, GPCRs regulate the expression of apoptosis signal regulating kinase-1 (ASK1), mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) by activating Gα [28]. Meanwhile, Gβγ also promotes the activation of phosphatase C (PLC), phosphatidylinositol 3-kinase (PI3K), triphosphate inositol (IP3), phospholipaseA2 (PLA2), protein kinase B (PKB), and prostaglandin (PG). Similarly, the CB2R plays an immunomodulatory role by activating a range of signals. It has been confirmed that CB2R needs to bind with Gi/o to inhibit adenylate cyclase (AC), reduce cAMP concentration and activate MAPK [29]. The complex generated by CB2R with N-Archidonoyl-ethanolamide (AEA) can activate of PLC and IP3, leading to the release of Ca2+ and K+ within cells [30]. Furthermore, CB2R can couple with G protein to induce p38 phosphorylation and activate cAMP-response elation binding protein (CREB). Ultimately, the activation of CB2R results in the secretion of various cytokines, like IL-6 and IL-10, in human primary leukocytes [29], [31], [32], while also reducing the expression of IL-17, IFN-γ, TNF-α, IL-6 and IL-12 in immune function cells [31], leading to an anti-inflammatory effect (Fig. 2).

Cannabinoid ligands can be classified as agonists and antagonists based on their different functions for the cannabinoid receptors and intrinsic activity. Agonists facilitate the stabilization of the conformational state of the receptor that promote the activation of downstream signaling pathways, then produce biological effects. Nevertheless, antagonists facilitate the stable conformational state that reduce or prevent the activation of downstream signaling pathways, and also prevent agonist binding to the receptor or inhibit signal-activated receptor conformational changes.

CB2R has emerged as an attractive drug target for the treatment of related disease. To date, a large amount of CB2R ligands have been reported, encompassing endogenous ligands, natural products, and small molecules [33]. Most of the current research has focused on the development of selective CB2R agonists, but only a limited fraction of ligands have progressed to clinical trials due to their poor selectivity [34]. In this review, we present a summary of recent advancements in CB2R ligands research, including endogenous ligands, natural products, and small molecules. Additionally, we offer insights into the potential development of specific active compounds targeting CB2R.