Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor

Abstract

The cannabinoid type-1 (CB 1) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB 1 receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB 1 orthosteric ligands into druggable candidates. The difficulty is mainly due to the adverse effects associated with orthosteric CB 1 ligands. Recent discoveries of allosteric CB 1 modulators provide tremendous opportunities to develop CB 1 ligands with novel mechanisms of action; these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB 1 receptor. In this paper, we review and summarize the complex pharmacological profiles of each class of CB 1 allosteric modulators, the development of new classes of CB 1 allosteric modulators and the results from in vivo assessments of their therapeutic value.

Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

“…Org27569, ZCZ011, and GAT211 share in common a 2- and 3-alkyl-group-substituted indole ring (indole-2-carboxamides) (Price et al, 2005; Ahn et al, 2012; Cawston et al, 2015; Ignatowska-Jankowska et al, 2015; Laprairie et al, 2017), suggesting this is an important structural requirement for allosteric modulators of CB1R (reviewed in Lu et al, 2018) (Figure 1). CB1R allosteric modulator activity is maintained or improved by C-5 substitution of Org27569 and GAT211 (Cawston et al, 2015; Hurst et al, 2019).…”

“…Further, Cawston et al (2015) recently demonstrated that varying the substituents around indole-2-carboxamides can affect the temporal activity of Org27569 derivatives, without affecting the NAM activity these compounds have on CB1R-mediated signaling. Based on the presence of an indole-2-carboxamide, and literature demonstrating the potential actions that might indicate an undocumented CB1R allosteric modulatory activity (Cawston et al, 2015; Lu et al, 2018), we identified indomethacin as a potential allosteric modulator of CB1R.…”

Cannabis, cannabinoid receptors, and endocannabinoid system: yesterday, today, and tomorrow

“…In the review article entitled "Translational potential of allosteric modulators targeting the cannabinoid CB 1 receptor", the authors discuss recent advances in structural and mechanistic studies on CB 1 R allosteric modulators. They suggest that allosteric CB 1 modulators provide tremendous opportunities to develop CB 1 ligands with novel mechanisms of action; these ligands potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB 1 receptor [6]. In a research article "Identification of novel mouse and rat CB 1 R isoforms and in silico modeling of human CB 1 R for peripheral cannabinoid therapeutics", the authors provide experimental evidence that human CB 1 R has a special isoform in peripheral but not in the CNS (called peripherally enriched CB 1 isoforms), but this feature does not exist in rodents [7].…”

Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities

“…The ligands interacting with CB1R can be classified according to their origin (endocannabinoids, phytocannabinoids, or synthetic cannabimimetics), chemical structure (e.g., indole, urea, or tropane derivatives) and psychoactive (psychotropic and non-psychotropic) effect [41]. Hence, CB1R can be activated by an endocannabinoid agonist such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), synthetic cannabimimetics (e.g., CP 55,940 and HU-210), or exogenous agonists like ∆-9-tetrahydrocannabinol (THC), a phytocannabinoid responsible for a psychoactive action of marihuana; synthetic inverse agonist/antagonists (e.g., SR-141716A and AM251), and neutral antagonist (e.g., AM6545) [11,15]. All of these aforementioned ligands are orthosteric ligands.…”

“…Cannabinoid receptor type 1 (CB1R) is the most abundant GPCR, of the class A receptor, expressed mainly in neurons in the central nervous system [9,10,11]. It is one of the two best-known receptors of the cannabinoids and is an integral part of the endocannabinoid (ECS) system.…”