# Biosynthesis of Nature-Inspired Unnatural Cannabinoidss
## 5 CB Receptors and Their Ligands
### Orphan GPCRs and Other Cannabinoid-Related GPCRs  
Several GPCRs have also been implicated as targets, but none has been IUPHAR designated as cannabinoid receptors, mainly because of data inconsistencies in the pharmacological literature [117]. GPR3, GPR6, and GPR12 share over 60% sequence similarity and are phylogenetically close to CB1 and CB2, belonging to the same MECA cluster (melanocortin, endothelial differentiation, cannabinoid, adenosine GPCRs). They are largely expressed in the brain and the reproductive system and thus, are involved in regulations of various neurological and reproductive processes. GPR3 and GPR6 notably have been reported to recognize CBD [118]. There are several other phylogenetically close GPCRs such as the recently deorphanized free fatty acid receptors and several other orphan receptors [119].  
Besides the phylogenetically related GPCRs, more distant receptors such as GPR18 and GPR55 (13% sequence identity to CB1 for both) have also been studied with respect to cannabinoid binding and have been implicated in overlapping pathophysiological processes with CB1 and CB2 [117]. GPR55 is predominantly expressed in the brain and peripheral systems [120; 121; 122]. It has been shown to bind lysophospholipids [123], while for cannabinoids, some studies report \(\Delta^{9}\)-THC activation [124; 125], but functional assays are not consistent [126; 127]. GPR18 is highly expressed in lymphoid tissues and moderately in reproductive and several internal organs [128; 129]. It has been reported to endogenously bind N-arachidonoyl glycine [129; 130] (disputedly, [131]) and Resolvin D2, as well as various cannabinoids [132; 133]. None of the abovementioned orphan GPCRs have been resolved structurally, although phylogenetically related GPR3, GPR6, and GPR12 can be  
Figure 15: (\(-\))-trans-\(\Delta^{9}\)- THC structural numbering and functional groups.  
modelled with homology modelling tools with reasonable accuracy, due to their relatively high level of sequence identity to solved structures of CB1 and CB2.  
CB1 and CB2 themselves may form heterodimers with other GPCRs such as D2 [134; 135], CXCR4 [136], or even the abovementioned orphan GPR55 [137], among others [117]. How heterodimer affects ligand binding directly is not well understood, but oligomerization context has to be considered for therapeutic drug screening efforts. One aminoalkylindole strong cannabinoid agonist WIN55,212-2 has been reported to bind to other GPCRs, dubbed collectively as alkylindole (AI)-sensitive. Likewise, several endocannabinoids, phytocannabinoids, and synthetic cannabinoids have been shown to bind to other GPCRs [138; 139; 140]. Such cross-talks make neat categorization challenging, but merit consideration.  
With diversified libraries of unnatural cannabinoids, it might be desirable to include the less-explored cannabinoid-related GPCRs, or even cannabinoid-binding non-GPCRs, in screening exercises. The emergence of an abundance of unnatural cannabinoid structures with recent metabolic engineering of the cannabinoid biosynthetic pathway may necessitate virtual screening of these unnatural cannabinoids to aid in experimental screening, for instance, by paring down candidates with interaction to these receptors, or to explain mechanisms. Furthermore, investigation of these receptors, if they truly recognize cannabinoids and transduce downstream signals, would shed light on the endocannabinoid system at large, and aid in the discovery and design of novel therapeutic cannabinoids.