Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity

Soethoudt, Marjolein; Grether, Uwe; Fingerle, Juergen; Grim, Travis W.; Fezza, Filomena; Petrocellis, Luciano De; Ullmer, Christoph; Rothenhäusler, Benno; Perret, Camille; Gils, Noortje van; Finlay, David B.; Macdonald, Courtney; Chicca, Andrea; Gens, Marianela Dalghi; Stuart, Jordyn; Vries, Henk de; Mastrangelo, Nicolina; Xia, Lizi; Alachouzos, Georgios; Baggelaar, Marc P.; Martella, Andrea; Mock, Elliot D.; Deng, Hui; Heitman, Laura H.; Connor, Mark; Marzo, Vincenzo Di; Gertsch, Jürg; Lichtman, Aron H.; Maccarrone, Mauro; Pacher, Pál; Glass, Michelle; Stelt, Mario van der

doi:10.1038/ncomms13958

Cited by 291 publications

(427 citation statements)

References 64 publications

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“…These studies and others indicate that the CB 2 receptor is up-regulated in response to immune cell activation and inflammation (Klein, 2005; Stella, 2010). More recently, CB 2 receptor expression has been reported in the healthy CNS (Van Sickle et al, 2005), although its presence in adult native brain tissue remains somewhat controversial (Atwood & Mackie, 2010; Soethoudt et al, 2017). …”

Section: Distributionmentioning

confidence: 99%

CB 1 and CB 2 Receptor Pharmacology

Howlett

Abood

2017

Advances in Pharmacology

272

219

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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 is considered.

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Section: Distributionmentioning

confidence: 99%

CB 1 and CB 2 Receptor Pharmacology

Howlett

Abood

2017

Advances in Pharmacology

272

219

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“…CB2 is activated by compounds such AM1241, JWH-133, HU-910, and HU-308 [26]; in addition, there are compounds without special selectivity for either cannabinoid receptor, such as HU-210, CP 55,940, and R-(+)-WIN 55,212-2. On the other hand, there are CB1 antagonists such as SR141716A and AM251; and CB2 antagonists such as SR144528 and AM630 [14,26] (Fig. 1).…”

Section: Cb1 and Cb2 And Physiological Regulationmentioning

confidence: 99%

Immunoregulatory Role of Cannabinoids during Infectious Disease

Hernández-Cervantes

Méndez-Dı́az²,

Prospéro-Garcı́a³

et al. 2017

Neuroimmunomodulation

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Although the endocannabinoid system (ECS) is involved in the regulation of several physiological processes, including sleep and the immune response, its role during infections has not been fully studied. It is well known that the use of this drug increases susceptibility to infections because of the impact on the modulation of the immune system. Concerning the medicinal or recreational use of marijuana, its influence on the course of an infection, whether this has been caused by bacteria, viruses, parasites, and to a lesser degree, fungi, has been reported. Furthermore, there is evidence suggesting the involvement of the ECS in the control and elimination of infectious agents such as bacteria, viruses, and some protozoa; in the case of fungi, few studies are available so far. The purpose of this review is to present the existing studies related to infections and the ECS, the microbicidal effects of compounds isolated from Cannabis sativa, and the association between marijuana use and the development of rare pathologies in specific diseases.

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“…31 We found no effect of the CB2R agonist, JWH-133, on PTZ-induced seizures (Figure 4). [46][47][48] The doses of JWH-133 and SR144528 used in this study were selected because they had been previously shown to elicit effects in the brain in other models of neurological disorders. [29][30][31][32][33] We selected JWH-133 and SR144528 for our studies because they are highly potent and CB2R-specific, F I G U R E 6 Deletion of CB2Rs does not worsen flurothyl-induced seizures in Scn1a RH/+ mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

2019

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Objective: The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body. Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A. The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility. Methods: We examined susceptibility to induced seizures using a number of paradigms in CB2R knockout mice (Cnr2 −/− ), and determined the effects of the CB2R agonist, JWH-133, and the CB2R antagonist, SR144528, on seizure susceptibility in wild-type mice. We also examined seizure susceptibility in Cnr2 mutants harboring the human SCN1A R1648H (RH) epilepsy mutation and performed Electroencephalography (EEG) analysis to determine whether the loss of CB2Rs would increase spontaneous seizure frequency in Scn1a RH mutant mice. Results: Both heterozygous (Cnr2 +/− ) and homozygous (Cnr2 −/− ) knockout mice exhibited increased susceptibility to pentylenetetrazole (PTZ)-induced seizures. The CB2R agonist JWH-133 did not significantly alter seizure susceptibility in wildtype mice; however, administration of the CB2R antagonist SR144528 resulted in increased susceptibility to PTZ-induced seizures. In offspring from a cross between the Cnr2 × RH lines, both Cnr2 and RH mutants were susceptible to PTZ-induced seizures; however, seizure susceptibility was not significantly increased in mutants expressing both mutations. No spontaneous seizures were observed in either RH or Cnr2/RH mutants during 336-504 hours of continuous EEG recordings. Significance: Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy. K E Y W O R D Scannabinoid 2 receptor, CB2R agonist, CB2R antagonist, SCN1A, seizure susceptibility 2360 | SHAPIRO et Al.

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Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity

Cited by 291 publications

References 64 publications

CB 1 and CB 2 Receptor Pharmacology

CB 1 and CB 2 Receptor Pharmacology

Immunoregulatory Role of Cannabinoids during Infectious Disease

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

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