# \(\beta\)-Caryophyllene: A Sesquiterpene with Countless Biological Properties
## 1 Introduction  
Sesquiterrepoids are an extremely wide group of secondary metabolites found in the plant kingdom [1; 2]. Their main carbon backbone consists of 15 atoms and several synthases action leads to a great variety of chemical structures. In particular, bicyclic sesquiterpenoids have raised attention in the bio-pharmacological field, even as essential oils. Among them, \(\beta\)-caryophyllene is one of the major component of essential oils extracted from spice and food plants [3; 4; 5; 6; 7], such as black pepper (_Piper nigrum_ L.), rosomary (_Rosmarinus officinalis_), cinnamon (_Cinnamoun_ spp. )oregano (_Origanum vulgare_ L.) basil (_Ocimum_ spp. ), thyme (_Thymus vulgaris_), sage (_Salvia officinalis_), mint (_Mentha piperita_), ginger (_Zingiber officinal_), chinotto (_Citrus Myrrtfolia_ Raf) [8], and cloves (_Syzygium aromaticum_) [9; 10]. It was also found in citronella, (_Cymbopogon_), pine tree (_Pinus_), _Chenopodium ambrosioides, Camabis sativa_, in plants of the genus _Copaifera_, _Artemisia_, _Murraya_, _Cordia_, _Spiranthes_, _Ocimum_, _Croton_[9; 10], and in the leaves of _Anmonia Cherimola_[11]. This plant compound was approved by Food and Drug Administration (FDA) and European Food Safety Authority (EFSA) and it is used as flavour enhancer [9] and in cosmetics [12]. In nature, BCP mainly occurs as _trans_-caryophyllene ((E)-BCP) (**1**) mixed with small amount of the isomers (Z)-\(\beta\)-caryophyllene ((Z)-BCP) (**2**) and \(\alpha\)-humulene (\(\alpha\)-caryophyllene) (**3**) [12], and its oxidation derivative, \(\beta\)-caryophyllene oxide (BCPO) (**4**) (Figure 1). BCP belongs to cannabinoid family, which are ligands of the cannabinoid receptors present in the organism. Cannabinoid receptors CB1-R and CB2-R are metabotropic receptors are G protein (protein binding GTP)-coupled receptors, involved in the regulation of neurotransmitters responsible for maintaining an energetic balance, in the metabolism, and in the immune response. The aforementioned receptors are bound and activated by endogenous cannabinoids, derivatives of arachidonic acid, including 2-arachidonoylglycerol and \(N\)-arachidonoylethanolamine, better known as anandamide. Both receptors are bound by a lot of proteins in various pathways, acting as mediators of cellular responses to biological molecules. Unlike the main traditional cannabinoids, such as \(\Delta^{8}\)-tetrahydrocannabinol (**5**), \(\Delta^{9}\)-tetrahydrocannabinol (**6**) and cannabinoid (**7**) (Figure 2), able to activate both receptors, BCP has a very different chemical structure and it is a selective agonist of CB2-R. Furthermore, BCP has no side effects, not activating CB1-Rs (mainly expressed in the central nervous system, but also in the liver, lungs, heart, blood vessels and digestive tract). CB2-Rs are mainly found in peripheral tissues and in immune system cells (B and NK lymphocytes, macrophages, mast cells) and, to a lesser extent, in the central nervous system (brain, neurons, microglia) [13]. The expression of CB2-Rs in the central nervous system is increased in neurodegenerative pathologies, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and in some tumours like gliomas [14]. The binding of BCP to CB2-Rs is responsible for many cellular events:  
* The activation of G\({}_{\text{i/o}}\)\(\alpha\)-subunit inhibits the activity of adenylate cyclase, the enzyme which converts ATP in cAMP (cyclic AMP) and activates phospholipase C (PLC), determining calcium release from IP3 (inositol trisphosphate)-sensitive calcium channels, increasing the intracellular level of calcium;
* The activation of the complex formed by G\({}_{\text{i/o}}\)\(\beta\)- and \(\gamma\)-subunits, which modulate various pathways modifying the expression and the activity of many target proteins [15]. Figure 1: Structures of sesquiterpenes (**1–4**).