Cannabinoid 1 Receptor

Cannabinoids and Their Receptors

Abhijit R. Kulkarni , ... Ganesh A. Thakur , in Methods in Enzymology, 2017

4 Summary and Future Directions

CB1R, the principal GPCR in mammalian brain, is involved in several (patho)physiological processes affecting humans and has been considered a promising therapeutic target by both academia and the pharmaceutical industry. Orthosteric CB1R antagonists/inverse agonists have been pursued in the clinic as novel therapeutics for treating diseases such as obesity, nicotine addiction, and metabolic syndrome. However, adverse events associated with them have prompted alternative, chemical pharmacology approaches for leveraging the translational potential of drug-like small molecules that modulate CB1R-dependent signaling. In this regard, CB1R NAMs are expected to garner continued interest by offering a potentially safer therapeutic avenue for attenuating CB1R-dependent signaling with improved safety, efficacy, and tolerance.

Research in the area of CB1R allosteric modulators over the past decade has improved our understanding of the structural requirements for CB1R NAM activity and has led to the identification of some potent and efficacious CB1R NAMs. However, there is a paucity of their in vivo profiling data. A major limitation associated with the two prototypical CB1R NAMs, Org27569 and PSNCBAM-1, is that they exhibit CB1R inverse agonism in addition to NAM activity. Current SAR studies, however, have only partially addressed strategies for minimizing the inverse agonist activity of these compounds at CB1R. Identification of potent and efficacious CB1R NAMs lacking inverse agonism, as well as those exhibiting functional selectivity with drug-like physicochemical properties, may provide a tenable approach toward resolving the beneficial and deleterious routes of CB1R information output and reduce the side-effect risk of modulating/attenuating CB1R signaling.

Research over the past two decades on CB1R orthosteric agonists has demonstrated their (pre)clinical efficacy against neuropathic pain, glaucoma, neurodegenerative disorders, and posttraumatic stress. However, as with CB1R orthosteric antagonists, the unacceptable adverse event risk associated with typical orthosteric CB1R agonists has plagued their development as drugs and effectively dampened their commercial appeal. Alternative therapeutic strategies to address these issues such as development of inhibitors of endocannabinoid-metabolizing enzymes (FAAH and MGL) have also met with limited success and clinical traction. Currently available data on CB1R PAMs from animal studies suggest their effectiveness in treating conditions such as neuropathic pain and glaucoma without producing psychomimetic side effects. Thus, due to their greater receptor selectivity and finer control over downstream signaling than standard CB1R orthosteric agonists, CB1R PAMs are expected to gain particularly intense interest as a therapeutic modality.

A recent breakthrough in cannabinoid GPCR structural biology has been the atomic resolution of two CB1R crystal states (Hua et al., 2016; Shao et al., 2016). However, GPCR crystal structures, in general, cannot offer much insight into the character of GPCR/CB1R allosteric site(s) and the structure–function correlates underlying the allosteric modulator phenotypes. Site-directed mutagenesis together with in silico studies has provided some information on important amino acids at CB1R allosteric site(s) as ligand-interaction sites. CB1R-specific allosteric covalent probes from both indole-2-carboxamides and diaryl urea scaffolds have been synthesized and characterized. Their availability enables additional experimental studies aimed at further experimental characterization of CB1R allosteric ligand-binding motifs and the pharmacology of CB1R functional modulation by irreversible/covalent ligands. Such probes can potentially be used to stabilize allosteric CB1R conformations to aid their crystallization for further atomic-level X-ray CB1R structure analyses. Structure-based drug discovery efforts emerging from improved characterization of CB1R allosteric site(s) and structure–function correlates of CB1R-negative and -positive modulation of CB1R conformation will significantly impact the development and advancement of allosteric modulator as CB1R-targeted therapeutics.

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Retinal Cannabinoids

S. Yazulla , in Encyclopedia of the Eye, 2010

Localization – Cannabinoid Receptors

CB1Rs have been localized by immunohistochemistry in the retinas of numerous species, including human, monkey, mouse, rat, chick, salamander, and goldfish. Despite differences in detail, there is a common theme. In general, the most prominent label is in cells of the through pathway: photoreceptors, bipolar cells, and ganglion cells. Cone pedicles in all species contain CB1Rs. Rod spherules appear to be labeled in all species except goldfish. Ultrastructural analysis has been performed exclusively on goldfish cones. CB1R-IR is on plasma membrane at the perimeter of the pedicle as well as within the invagination. CB1R-IR is not immediately apposed to the synaptic ribbon, but is at some distance from it. Regarding bipolar cells in mammals, CB1R-IR is restricted to rod bipolar cells as confirmed by double labeling with antisera against PKC. In goldfish, there is a higher proportion (∼3:1) of CB1R-IR in ON bipolar cells compared to OFF bipolar cells. This difference holds for mixed rod–cone bipolar cells as well as for cone bipolar cells. CB1R-IR, on the bipolar cell synaptic terminal membrane, is not adjacent to the synaptic ribbons. Rather, the CB1R-IR is always some distance removed from the ribbon, the same as observed for the cone pedicles.

Regarding rat horizontal cells, CB1R-IR is confined to the cell bodies and is not present on the dendrites, unlike bipolar cells. CB1R-IR is also found on a population of large amacrine cells, identified in rat as a rare type that is immunoreactive for PKC and GABA. In goldfish, CB1R-IR is on presynaptic membrane of amacrine cell boutons. These boutons appear throughout the depth of the inner plexiform layer and are presynaptic to bipolar cell terminals and small processes derived from ganglion cells. It is likely that these CB1R-immunoreactive processes are from a single type of diffuse amacrine cell.

CB1R-IR is on Müller's cells in goldfish but not in any other preparation. There are inconsistent reports of CB1R-IR in mammalian astrocytes, microglia, and oligodendrocytes. Activation of CB1Rs inhibits excitatory amino acid transport and induces glutamate release from astrocytes in the mammalian brain. CB1R and CB2R are involved in gliotic responses to injury. The interaction of eCBs and glia has not been investigated in the retina. CB2 mRNA was described in all cellular layers of the rat retina; this could include glial labeling, particularly Müller's cells.

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Cannabinoids

S.H. Fox , in Encyclopedia of Movement Disorders, 2010

Cannabinoid CB1 Receptors

CB1 receptors are widely distributed in both the peripheral and central nervous system. Cannabinomimetic effects are related to CB1 receptors within particular brain regions.

Memory

CB1 receptors are located in the hippocampus, particularly in CA3 field of Ammon's horn and the molecular layer of the dendate gyrus.

Analgesia

CB1 receptors are located on the peripheral terminals of primary sensory neurons and in the dorsal horn of the spinal cord, in addition to the central sites that may mediate pain including amygdala, thalamus, superior colliculus, and rostral ventromedial medulla.

Thermoregulation

CB1 receptors are located within the hypothalamus.

Antiemetic

CB1 receptors are located in the dorsal vagal complex, consisting of the area postrema (the chemoreceptor trigger zone for emetic reflexes), nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem.

Motor functions

The basal ganglia have one of the highest concentrations of CB1 receptors in brain. CB1 receptors are located on the presynaptic terminals of the GABAergic striatopallidal pathways in the globus pallidus (GP) (both internal (GPi) and external (GPe) segments) and the substantia nigra pars reticulata (SNpr). In addition, CB1 receptors are found on the corticostriatal glutamatergic projection neurons as well as paravalbumin positive interneurons of the striatum. In the cerebellum, CB1 receptors are located in the molecular layer, which contains the fibers and dendritic processes from Purkinje cells.

Other locations

CB1 receptors are also found in the periphery in vasculature, heart, bladder, and small intestine and vas deferens.

Several synthetic cannabinoids are now available ( Table 1 and Table 2 ).

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Adolescent neurocognitive development and cannabis use

B. Tervo-Clemmens , ... B. Luna , in Factors Affecting Neurodevelopment, 2021

The endocannabinoid system and development

CB1 receptors have been implicated in various normative developmental processes, ranging from embryonic development to aging (Fernández-Ruiz, Berrendero, Hernández, & Ramos, 2000), and a burgeoning literature focuses on developmental changes in CB1 receptors during adolescence. However, due to the invasive nature of the approaches required to identify receptor binding and expression, there are limited human studies of CB1 receptors in adolescents. Nevertheless, studies from rodents have identified developmental changes in CB1 expression during puberty (de Fonseca Rodríguez, Ramos, Bonnin, & Fernández-Ruiz, 1993), and existing research from nonhuman primates suggests specific maturational changes in CB1 receptors in the prefrontal cortex (Eggan, Mizoguchi, Stoyak, & Lewis, 2009).

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Cannabinoids and Their Receptors

Caitlin E. Scott , Debra A. Kendall , in Methods in Enzymology, 2017

Abstract

The cannabinoid CB1 receptor is abundant in the central nervous system and regulates neuronal transmission and other key physiological processes including those leading to pain, inflammation, memory, and feeding behavior. CB1 is activated by the endogenous ligands, arachidonoyl ethanolamine and 2-arachidonoyl glycerol, by various synthetic ligands (e.g., CP55940), and by Δ9-tetrahydrocannabinol, the psychoactive component of Cannabis sativa. These CB1 ligands are orthosteric and transduce downstream signals by binding CB1 and primarily inducing Gi coupling, but Gs and β-arrestin coupling are also possible. Recently, allosteric modulators for CB1 were discovered that bind to topographically distinct sites and can noncompetitively impact the potency and efficacy of orthosteric compounds. These offer the exciting potential for mechanistic analyses and for developing therapeutics. Yet, it is critical to elucidate whether a compound is a positive allosteric modulator or a negative allosteric modulator of orthosteric ligand-induced CB1 profiles to understand pathway specificity and ameliorate diseases. In this chapter, we present equilibrium and kinetic binding analysis to reveal the impact of allosteric modulators on CB1. Also described are activities consistent with CB1 activation (or inactivation) and include cellular internalization of CB1 and downstream signaling patterns. Since many CB1 allosteric modulators do not enhance G protein coupling, it is critical to distinguish CB1 activation and biased signaling patterns via β-arrestin from CB1 inactivation. These strategies can illuminate pathway specificity and are valuable for the fine-tuning of CB1 function.

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Cannabinoids and the Brain: The Effects of Endogenous and Exogenous Cannabinoids on Brain Systems and Function

David L. Atkinson , Jeff K. Abbott , in The Complex Connection Between Cannabis and Schizophrenia, 2018

CB1 Receptors

CB1 receptors are expressed in the hippocampus, mesolimbic dopamine areas (ventral tegmental area and nucleus accumbens), cingulate cortex, prefrontal cortex, and cerebellum. The wide distribution of these receptors may help to explain the diverse effects of manipulating the endocannabinoid signaling system. CB1 receptors are g-coupled receptors, and in fact are the most prominent gi/0 receptors in the human central nervous system (CNS). Gi/0 proteins downregulate cyclic adenosine monophosphate (cAMP). CB1 agonism also activates the mitogen-activated protein (MAP) kinase intracellular signaling pathways. The intracellular workings of CB1 are largely beyond the scope of this chapter, but CB1 receptors are also present in mitochondria, where they may exert effects on memory formation (Hebert-Chatelain et al., 2016).

CB1 receptors largely act on presynaptic neurons by decreasing GABA release. This can lead to a net facilitation of dopamine release, as in the ventral tegmental area, when the reduction of inhibitory, GABAergic tone facilitates phasic, burst firing of dopamine (Laricchiuta, Musella, Rossi, & Centonze, 2014). However, in certain brain areas, such as the hippocampus, the CB1 receptor acts as an excitatory receptor by increasing glutamate. CB1 receptors are also found in astrocytes and glia, in addition to the signaling neurons, and the receptors may be found inside of the cell (Busquets Garcia et al., 2016). In short, given the widespread distribution in the brain, as well as among different cell types, CB1 receptors mediate diverse effects. To summarize, CB1 receptors are responsible for maintaining a delicate balance between neuronal inhibition and excitation, especially in GABAergic, glutamatergic, and dopaminergic transmission (Fig. 2).

Fig. 2. Schematic of cannabinoid modulation of dopamine release through differential actions of glutamate and GABA.

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Endocannabinoids

David A. Greenberg , in Encyclopedia of the Neurological Sciences, 2003

Cannabinoid Receptors

Two cannabinoid receptors, CB1 and CB2, have been identified. CB1 receptors are predominantly neuronal but may also be found on vascular endothelial and smooth muscle cells, whereas CB2 receptors are located on nonneural cells. Both CB1 and CB2 receptors belong to the family of G (guanine nucleotide-binding) protein-coupled receptors, which have seven membrane-spanning regions. Beyond this, however, the human CB1 and CB2 receptors are structurally distinct and show only 44% sequence homology at the amino acid level.

CB1 and CB2 receptors are coupled to inhibitory G proteins, and their activation reduces adenylate cyclase activity and decreases formation of cyclic AMP. Receptor-mediated effects of cannabinoids on other enzymes and ion channels have also been demonstrated. One of the most widely studied effects of CB1 receptor activation is the inhibition of voltage-gated calcium flux into N- and P/Q-type, voltage-gated calcium channels. This interaction may permit endocannabinoids to regulate the release of neurotransmitters such as glutamate and GABA.

Anandamide and 2-AG, like THC and various synthetic cannabinoid agonists, activate both CB1 and CB2 receptors. However, selective antagonists can discriminate between CB1 and CB2 receptors and have been used to determine which receptor subtype mediates the various biological actions of cannabinoids. Endocannabinoids are also reported to interact with vanilloid VR1 (capsaicin) receptors.

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Multiple Sclerosis and Related Disorders

Bruce A.C. Cree , in Handbook of Clinical Neurology, 2014

Cannabinoid receptor 1 (CB1)

CB1 modulates severity in experimental allergic encephalomyelitis and may have a neuroprotective role in response to inflammation (Rossi et al., 2011). A case (n  =   143)-control (n  =   98) study of an AAT repeat microsatellite near the CB1 receptor gene found a putative association of the 7/8 genoytpe with PPMS patients (n  =   47) versus healthy controls (p  =   0.016) in a Spanish dataset (Ramil et al., 2010). This association did not retain statistical significance after correction for multiple comparisons.

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Retinal Cannabinoids☆

Bruno Cécyre , ... Jean-François Bouchard , in Reference Module in Neuroscience and Biobehavioral Psychology, 2017

Localization—Cannabinoid Receptors

CB1R was extensively studied in the retina of various species using techniques such as in situ hybridization, reverse transcription polymerase chain reaction (RT-PCR), western blot or immunohistochemistry. CB1R was first localized in the ganglion cell layer (GCL) and inner nuclear layer (INL) of the rat retina. Since then, CB1R expression was detected in the retinas of human, monkey, mouse, rat, chick, salamander and goldfish with a similar labeling in the outer plexiform layer (OPL), inner plexiform layer (IPL) and GCL. Briefly, CB1R is expressed in the inner and outer segments of photoreceptors with a strong labeling in the cone pedicles; in the membrane but not in dendrites of horizontal cells; in the dendrites, cell body axons of rod bipolar cells; in GABAergic and other amacrine cells; in the synapses of rod and cone bipolar cells; in the cell body and fibers of ganglion cells. CB1R is also expressed in Müller cells but only for the goldfish.

The localization of CB2R in the retina has been less extensively studied than CB1R. It was first believed that CB2R was not expressed in the embryonic and adult retina. Then, CB2R mRNA localization was shown in photoreceptors, INL and GCL of the rat retina. Subsequent studies confirmed the presence of CB2R in the retina, but with a differential expression between species. CB2R is expressed in the inner and outer segments of photoreceptors, with an absence of labeling in the cone pedicles; in the membrane of the soma and in the dendrites of horizontal cells; in the membrane of the some of cone and rod bipolar cells, and in axons of rod bipolar cells; in unspecified subtypes of amacrine cells; in the soma of ganglion cells. CB2R is absent from Müller cells for most species, while in the vervet monkey it is exclusively present in these cells.

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CB-1 Cannabinoid Receptor

Steve P.H. Alexander , in xPharm: The Comprehensive Pharmacology Reference, 2007

Endogenous Regulation

Developmental Expression

CB1 cannabinoid receptor mRNA in the rat brain appears to show a distinct developmental profile to radioligand binding, in that mRNA levels are at adult levels at postnatal day 3. Receptor number, on the other hand, doubles with increasing age, with some lag after mRNA levels achieving a plateau Mclaughlin (1994). From E11, CB1 receptor mRNA is apparent in the embryonic rat neuronal tube, and later in the CNS Buckley et al (1997). Message was also visible in sympathetic andparasympathetic ganglia, in the retina and in enteric ganglia of the alimentary system. High levels were also noted in the thyroid and adrenal glands.

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