Cannabinoid Receptors and Their Ligands: Ligand—Ligand and Ligand—Receptor Modeling Approaches

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

“…Cannabinoid receptor agonists occupy a common binding region within the CB 1 receptor, as demonstrated by their mutual competitive displacement in both radioligand binding assays (Showalter et al, 1996;Felder et al, 1998;Horn et al, 2003) and structure-activity relationship modelling (Shim et al, 1998). However; within the hypothesized binding region, mutagenesis (Song and Bonner, 1996;Chin et al, 1998;McAllister et al, 2003) and molecular modelling (Reggio, 2005;Shim and Howlett, 2006) have demonstrated that the aminoalkylindoles interact with a series of residues distinct from those targeted by classical, non-classical and eicosanoid agonists. Thus, WIN55,212-2 may be more efficacious than the non-classical cannabinoid agonist, CP55940, or the eicosanoids, in inducing or stabilizing a CB 1 receptor active state that is capable of recruiting G q/11 proteins in addition to the preferred G i/o proteins.…”

Mutation Studies of Ser7.39 and Ser2.60 in the Human CB1Cannabinoid Receptor: Evidence for a Serine-Induced Bend in CB1Transmembrane Helix 7

“…The CB 1 cannabinoid receptor is a member of the G-protein coupled receptor (GPCR) family 1A, which includes the CB 2 receptor and the prototype rhodopsin (Howlett et al, 2002;Reggio, 2005). The human CB 1 and CB 2 receptors share only 44% amino acid overall homology, with a higher homology (68%) within the seven transmembrane domains (Munro et al, 1993).…”

“…These results clearly suggest that Ser7.39, but not Ser2.60, plays a crucial role in mediating ligand specific interactions for CP55,940, HU210, and AM4056 at the human CB 1 receptor. Our modeling studies predict that Ser7.39 in a gϪ1 conformation may induce a helix bend in TMH7 that provides docking space for CP55,940 binding; the S7.39A mutation may alter this binding space, precluding CP55,940 binding.The CB 1 cannabinoid receptor is a member of the G-protein coupled receptor (GPCR) family 1A, which includes the CB 2 receptor and the prototype rhodopsin (Howlett et al, 2002;Reggio, 2005). The human CB 1 and CB 2 receptors share only 44% amino acid overall homology, with a higher homology (68%) within the seven transmembrane domains (Munro et al, 1993).…”

“…These include: classic cannabinoid agonists [such as (Ϫ)-trans-␦-9-tetrahydrocannabinol], nonclassic cannabinoid agonists (such as CP55,940), endocannabinoids (such as N-arachidonoylethanolamine, anandamide), aminoalkylindole (AAI) agonists (such as WIN55,212-2), and diaryl pyrazole antagonist/inverse agonists (such as SR141716A) (Picone et al, 2002). Computational and mutational studies have identified several key amino acid residues in discrete noncontiguous regions of the TMHs that contribute in forming ligand binding sites (Abood, 2005;Reggio, 2005). These include but are not limited to the Lys3.28 (192), involved in the binding of anandamide, CP55,940, HU210, and SR141716A but not WIN55,212-2 (Song and Bonner, 1996;Chin et al, 1998;Hurst et al, 2002) via a hydrogen bonding interaction with the ligand.…”

Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors

“…Using LC-MS/MS, Gelman et al (12) detected RVD-Hp␣ in mouse heart and brain tissues as well as in blood samples. Because CP55,940 shares an identical or at least closely overlapping CB 1 receptor binding site with the endocannabinoids AEA and 2-AG, as well as with the inverse agonist SR141716 (rimonabant) (13), it was suggested that Hp␣ partially interacts with the same binding pocket, also based on a recent in silico study using a CB 1 receptor homology model (14). However, experimental data showing binding interaction of Hp␣ and RVD-Hp␣ with CB receptor in defined expression systems are lacking.…”