CB2 Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?
01 Oct 2014-Molecular Pharmacology (American Society for Pharmacology and Experimental Therapeutics)-Vol. 86, Iss: 4, pp 430-437
TL;DR: This review summarizes the present knowledge of CB2 receptor signaling, localization, and regulation, and discusses the availability of genetic tools to study CB2 receptors and also provides an update on preclinical data on CB2 agonists in pain models.
Abstract: The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor–based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.
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TL;DR: It is believed that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
Abstract: The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
617 citations
Cites background from "CB2 Cannabinoid Receptors as a Ther..."
...Although the expression of the CB2R in the CNS and PNS is comparatively limited, it is undeniable that the CB2R plays an active role in neurological activities, such as nociception, drug addiction and ne roinflammation [55,56]....
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...On the other hand, CB2R is also attracting more interest, especially on the peripheral sites, where studies have shown its beneficial effects in various pathological conditions [55]....
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...Although the expression of the CB2R in the CNS and PNS is comparatively limited, it is undeniable that the CB2R plays an active role in neurological activities, such as nociception, drug addiction and neuroinflammation [55,56]....
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TL;DR: ECB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders.
Abstract: Endocannabinoid signalling affects the behavioural domains of acquired fear, anxiety and stress-coping by modulating synaptic functions in specific brain circuits. Lutz and colleagues discuss the cellular mechanisms involved in these effects and the potential for endocannabinoid-based therapies to treat anxiety and stress-related disorders.
319 citations
TL;DR: A cell type-specific plasticity mechanism in the hippocampus is described that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.
234 citations
Cites background from "CB2 Cannabinoid Receptors as a Ther..."
...Simultaneously, the CB2R has emerged as an important alternative target for certain illnesses with great therapeutic potential because it is not psychoactive in its mode of action (242, 372)....
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...Both CBRs have additionally been shown to affect cell migration by activating mitogen-activated protein kinase (MAPK)-signalling via Gi (242, 243)....
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TL;DR: The most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date is reported, identifying marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects.
Abstract: The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
233 citations
TL;DR: This chapter will discuss the pharmacological characterization, distribution, phylogeny, and signaling pathways of the CB1 and CB2 cannabinoid receptors, and the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.
Abstract: The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny, and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.
193 citations
References
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TL;DR: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined.
Abstract: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined in this
7,389 citations
TL;DR: A detailed analysis based on comprehensive, recent, industry-wide data is presented to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity and propose specific strategies that could have the most substantial impact in improving R &D productivity.
Abstract: The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.
2,901 citations
"CB2 Cannabinoid Receptors as a Ther..." refers background in this paper
...The high failure rate of agents in clinical trials has prompted a re-evaluation of the predictive reliability of this approach (Paul et al., 2010; Baxter et al., 2013)....
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TL;DR: It is considered premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, because pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging and other kinds of supporting evidence are still lacking.
Abstract: Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
2,619 citations
"CB2 Cannabinoid Receptors as a Ther..." refers background in this paper
...…caspase, as well as some potassium and calcium ion channels (Bouaboula et al., 1996; Pertwee, 1997; McAllister et al., 1999; Sugiura et al., 2000; Howlett et al., 2002; MolinaHolgado et al., 2002; Ehrhart et al., 2005; Herrera et al., 2005, 2006; Pertwee et al., 2010; Atwood et al., 2012a) (Fig....
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TL;DR: As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration, but enough information is available to cause concern.
Abstract: As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have not been well studied, enough information is available to cause concern.
2,069 citations
"CB2 Cannabinoid Receptors as a Ther..." refers background in this paper
...A major limitation for the therapeutic development of compounds that directly activate CB1 receptors is unwanted psychotropic effects (Volkow et al., 2014)....
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...A major limitation for the therapeutic development of compounds that directly activate CB1 receptors is unwanted psychotropic effects (Volkow et al., 2014)....
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Journal Article•
TL;DR: The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitized.
Abstract: G protein-coupled receptors (GPCRs) are seven transmembrane proteins that form the largest single family of integral membrane receptors. GPCRs transduce information provided by extracellular stimuli into intracellular second messengers via their coupling to heterotrimeric G proteins and the subsequent regulation of a diverse variety of effector systems. Agonist activation of GPCRs also initiates processes that are involved in the feedback desensitization of GPCR responsiveness, the internalization of GPCRs, and the coupling of GPCRs to heterotrimeric G protein-independent signal transduction pathways. GPCR desensitization occurs as a consequence of G protein uncoupling in response to phosphorylation by both second messenger-dependent protein kinases and G protein-coupled receptor kinases (GRKs). GRK-mediated receptor phosphorylation promotes the binding of beta-arrestins, which not only uncouple receptors from heterotrimeric G proteins but also target many GPCRs for internalization in clathrin-coated vesicles. beta-Arrestin-dependent endocytosis of GPCRs involves the direct interaction of the carboxyl-terminal tail domain of beta-arrestins with both beta-adaptin and clathrin. The focus of this review is the current and evolving understanding of the contribution of GRKs, beta-arrestins, and endocytosis to GPCR-specific patterns of desensitization and resensitization. In addition to their role as GPCR-specific endocytic adaptor proteins, beta-arrestins also serve as molecular scaffolds that foster the formation of alternative, heterotrimeric G protein-independent signal transduction complexes. Similar to what is observed for GPCR desensitization and resensitization, beta-arrestin-dependent GPCR internalization is involved in the intracellular compartmentalization of these protein complexes.
1,898 citations
"CB2 Cannabinoid Receptors as a Ther..." refers background in this paper
...Internalization CB2 as a Therapeutic Target 431 can play a role in downregulation of the GPCR’s ability to signal at the membrane (Ferguson, 2001)....
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