CB1 and CB2 receptors are experimentally known to couple with the pertussis toxin-sensitive inhibitory G protein (Gi) (106). The activation of these inhibitory G proteins by CB1 and CB2 agonists leads to the inhibition of adenylate cyclase and the cAMP pathway (107), which ultimately inhibits the activation of cAMP-dependent protein kinase (PKA). This inhibition reduced the PKA phosphorylation and leads to an enhanced outward potassium current (108). In addition, CB1 activation also inhibits N- and P/Q-type voltage-dependent Ca2+ channels (108). CB1 receptor activation also results in transient increase of intracellular free Ca2+. These findings suggest that cannabinoids can suppress neuronal excitability and play a key role in regulating neurotransmitter release (108). In addition, CB1 and CB2 receptors both are able to activate mitogen-activated protein kinases-1 and -2, including extracellular signal-regulated kinase-1 and -2, and c-Jun N-terminal kinase (109-111). The CB1 receptor can also interact with other proteins through G protein-independent pathways such as β-arrestins, adaptor protein AP-3, and the adaptor protein FAN to control receptor signaling or trafficking pathway.CB2 receptors are present in immune cells and modulate cytokine release, therefore; activation of B- and T-cell CB2 receptors by cannabinoids leads to the inhibition of adenylyl cyclase and a reduced response to immune challenge. Finally, CB2 receptor stimulation is also involved in the activation of serine/threonine-protein kinases such as protein kinase B that are involved in stimulating cell survival, migration and growth (113, 114).. Allosteric modulators of CB1
Several GPCRs have been shown to contain allosteric binding sites for endogenous/synthetic ligands, which are distinct from the agonist-binding (orthosteric) site. The binding of allosteric modulators leads to a conformational change of the receptor, which affects the affinity and/or efficacy of the orthosteric (endogenous) ligands, thereby provide strong mediator to modulate signaling pathway. The CB1 selective allosteric modulators include both positive allosteric modulator (PAM) and negative allosteric modulator (NAM) (Figure 1.12). Allosteric modulators (AMs) exhibit distinct therapeutic advantages over orthosteric ligands in terms of enhanced target specificity and reduced off-target side effects (121-123).
Organon research identified the first CB1 allosteric modulator as ORG 27569 and subsequently they synthesized series of ORG compounds such as ORG29647, and ORG27759. These all ORG compounds are known to be CB1 allosteric modulators (124, 125). Computational receptor modeling suggested that the ORG27569 binding site is located in the TMH3-6-7 region of the CB1 receptor, which is partially overlapped by the SR141716A binding site but extending extracellularly. Computational results suggest that Lys192 is part of the ORG27569 binding site, while Phe200 and Trp356 are not. Experimental results suggest that alone this compound can act as an agonist, increasing cAMP production in untreated and PTX-treated cells. Computational modeling also suggested that ORG27569’s most important interaction is with residue Phe379; this is likely because ORG27569 forms several aromatic stacking interactions with Phe379. Together, these aromatic interactions help position ORG27569 in the receptor, placing a significant amount of ORG27569’s steric bulk against the EC end of TMH6 (126). PSNCBAM-1 is another CB1 allosteric modulator, which behaves as a positive modulation of agonist binding. At up to 10 μM, PSNCBAM-1 had no effect on constitutive activity, which indicates that it does not act as an inverse agonist (127). Lipoxin A4 (LXA4) is a positive allosteric endocannabinoid of CB1 receptors. This compound can cross the blood-brain barrier and displace the in vivo binding of [125I]-RTI-55 in rat caudate, and it antagonizes the locomotor effects of cocaine (128). RTI-371 and other dopamine transporter inhibitors with a similar in vitro and in vivo pharmacological profile were shown to be positive allosteric modulators of the human CB1 receptor (129).
Considering the current major obstacles in cannabinoid-based drug discovery such as on- and off-target side effects associated with CB1 receptor in the CNS, the development of its allosteric modulators can avoid such side effects because of the distinct therapeutic properties of allosteric modulators in terms of receptor-selectivity and signaling-pathway-selectivity. However, detailed structural data on cellular pathways of 7-TMRs is still limited. Hence, computational methods play an important role for structural predictions of 7-TMRs as well as their binding to ligands.
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