Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction

Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.

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Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells

Mediators of Inflammation ◽

10.1155/2015/362126 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Lei Yang ◽

Fei-Fei Li ◽

Yu-Chen Han ◽

Bin Jia ◽

Yin Ding

Keyword(s):

Cannabinoid Receptor ◽

Osteosarcoma Cell ◽

Nuclear Factor ◽

Therapeutic Action ◽

Cb2 Receptor ◽

Cb1 Antagonist ◽

Anti Inflammatory ◽

Anti Inflammation ◽

Necrosis Factor ◽

Proinflammatory Factors

Cannabinoid Δ9-tetrahydrocannabinol (THC) is effective in treating osteoarthritis (OA), and the mechanism, however, is still elusive. Activation of cannabinoid receptor CB2 reduces inflammation; whether the activation CB2 is involved in THC-induced therapeutic action for OA is still unknown. Cofilin-1 is a cytoskeleton protein, participating in the inflammation of OA. In this study, MG-63 cells, an osteosarcoma cell-line, were exposed to lipopolysaccharide (LPS) to mimic the inflammation of OA. We hypothesized that the activation of CB2 is involved in THC-induced anti-inflammation in the MG-63 cells exposed to LPS, and the anti-inflammation is mediated by cofilin-1. We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factorα(TNF-α), interleukin- (IL-) 1β, IL-6, and IL-8, decreased nuclear factor-κB (NF-κB) expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells. However, administration of CB2 receptor antagonist or the CB2-siRNA, not CB1 antagonist AM251, partially abolished the THC-induced anti-inflammatory effects above. In addition, overexpression of cofilin-1 significantly reversed the THC-induced anti-inflammatory effects in MG-63 cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.

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Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

International Journal of Molecular Sciences ◽

10.3390/ijms21041423 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1423 ◽

Cited By ~ 3

Author(s):

Mohammad Zakir Hossain ◽

Hiroshi Ando ◽

Shumpei Unno ◽

Junichi Kitagawa

Keyword(s):

Neuropathic Pain ◽

Adverse Effects ◽

Orofacial Pain ◽

Cannabinoid Receptor ◽

Motor Impairment ◽

Cb1 Receptors ◽

Cannabinoid Receptor 2 ◽

Alternative Approaches ◽

Cb2 Receptors ◽

The Brain

Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.

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Inhibition of Inflammatory Hyperalgesia by Activation of Peripheral CB2Cannabinoid Receptors

Anesthesiology ◽

10.1097/00000542-200310000-00031 ◽

2003 ◽

Vol 99 (4) ◽

pp. 955-960 ◽

Cited By ~ 171

Author(s):

Aline Quartilho ◽

Heriberto P. Mata ◽

Mohab M. Ibrahim ◽

Todd W. Vanderah ◽

Frank Porreca ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Thermal Hyperalgesia ◽

Receptor Activation ◽

Cb1 Receptor ◽

Cb2 Receptor ◽

Inflammatory Hyperalgesia ◽

Selective Antagonist ◽

Receptor Agonists ◽

Cb2 Receptors ◽

Cns Effects

Background Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia. Methods Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251. Results AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection. Conclusions Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.

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CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory

Neural Plasticity ◽

10.1155/2016/9817089 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 29

Author(s):

Yong Li ◽

Jimok Kim

Keyword(s):

Working Memory ◽

Motor Activity ◽

Knockout Mice ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Spatial Working Memory ◽

Fear Memory ◽

Cb2 Receptor ◽

Cb2 Receptors

Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.

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High-Affinity, Selective σ Ligands of the 1,2,3,4-Tetrahydro-1,4′-silaspiro[naphthalene-1,4′-piperidine] Type: Syntheses, Structures, and Pharmacological Properties

ChemMedChem ◽

10.1002/cmdc.201100423 ◽

2011 ◽

Vol 7 (3) ◽

pp. 523-532 ◽

Cited By ~ 18

Author(s):

Reinhold Tacke ◽

Rüdiger Bertermann ◽

Christian Burschka ◽

Steffen Dörrich ◽

Markus Fischer ◽

...

Keyword(s):

Pharmacological Properties ◽

High Affinity

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WWL70 protects against chronic constriction injury-induced neuropathic pain in mice by cannabinoid receptor-independent mechanisms

Journal of Neuroinflammation ◽

10.1186/s12974-017-1045-9 ◽

2018 ◽

Vol 15 (1) ◽

Cited By ~ 11

Author(s):

Jie Wen ◽

Melissa Jones ◽

Mikiei Tanaka ◽

Prabhuanand Selvaraj ◽

Aviva J. Symes ◽

...

Keyword(s):

Neuropathic Pain ◽

Chronic Constriction Injury ◽

Cannabinoid Receptor

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Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2020-0219 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Masoumeh Gholami ◽

Jamal Amri ◽

Saeed Pazhoohan ◽

Mehdi Sadegh

Keyword(s):

Mortality Rate ◽

Receptor Antagonist ◽

Wistar Rats ◽

Echinacea Purpurea ◽

Root Extract ◽

Cb2 Receptor ◽

Kindling Model ◽

Male Wistar Rats ◽

Clonic Seizures ◽

Cb2 Receptors

Abstract Objective Phytocannabinoids beyond the Δ9-tetrahy-drocannabinol have shown anticonvulsive effects. Also, alkylamides from Echinacea purpurea have been proved as cannabinomimetics. We examined the effect of the hydroalcoholic root extract of E. purpurea on pentylenetetrazol (PTZ)-induced tonic–clonic seizures and kindling model of epileptogenesis and the involvement of CB2 receptors as the mediator of this effect. Methods Male Wistar rats (200 ± 20 g) were used. Single intraperitoneal (i.p.) injection of PTZ (80 mg/kg) was used to induce tonic–clonic seizures. The kindling model of epileptogenesis was induced by daily injections of PTZ (37 mg/kg; i.p. for 15 days). Latency and duration of the stages were monitored for analysis. The hydroalcoholic root extract of E. purpurea was injected (i.p.) 20 min before seizure induction at the doses of 10, 50, 100 and 200 mg/kg. CB2 receptor antagonist SR144528 was injected (0.1 mg/kg; i.p.) 20 min before the Echinacea injection. Results In the tonic–clonic model, pretreatment with E. purpurea at the doses of 100 and 200 mg/kg significantly increased latencies to S2–S6, while it significantly decreased S6 duration and mortality rate. SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly prevented the effects of the extract on S4–S6 latencies. In the kindling model, E. purpurea at the doses of 100 and 200 mg/kg significantly delayed epileptogenesis and decreased mortality rate, while SR144528 injection before the injection of 100 mg/kg of E. purpurea significantly blocked this effect of the extract. Conclusion These findings revealed the anticonvulsive and antiepileptogenesis effects of the E. purpurea root extract, which can be mediated by CB2 receptors.

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CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

10.21203/rs.2.22085/v1 ◽

2020 ◽

Author(s):

Rui Xu ◽

Fan Yang ◽

Lijuan Li ◽

Xiaohong Liu ◽

Xiaolu Lei ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Nerve Injury ◽

Intrathecal Injection ◽

Receptor Activation ◽

Cb2 Receptor ◽

Dorsal Spinal Cord ◽

P38mapk Pathway ◽

Dorsal Spinal

Abstract Background: The importance of P2X purinoceptors, CB2 receptor and microRNA-124(miR-124) in spinal cord microglia to the development of neuropathic pain was demonstrated in numerous previous studies. The upregulation of P2X4 and P2X7 receptors in spinal dorsal horn microglia is involved in the development of pain behavior caused by peripheral nerve injury. However, it is not clear whether the expression of P2X4 and P2X7 receptors at dorsal spinal cord will be influenced by CB2 receptor or miR-124 in rats after chronic sciatic nerve injury.Methods: Chronic constriction injury (CCI) of the sciatic nerve was performed in rats to induce neuropathic pain. Tests of the mechanical withdrawal threshold (MWT) were carried out to assess the response of the paw to mechanical stimulus. The expression of miR-124, P2X4, P2X7 and CB2 receptor were detected with RT-PCR. The protein expression of P2X4, P2X7 and CB2 receptor, RhoA, ROCK1, ROCK2, p-p38MAPK and p-NF-kappaBp65 was detected with Western blotting analysis. Results: Intrathecal administration of CB2 receptor agonist AM1241 significantly attenuated CCI-induced mechanical allodynia and significantly inhibited the increased expression of P2X4 and P2X7 receptors at the mRNA and protein levels, which imply that P2X4 and P2X7 receptors expression are down-regulated by AM1241 in CCI rats. Western blot analysis showed that AM1241 suppressed the elevated expression of RhoA, ROCK1, ROCK2, p-p38MAPK and NF-κBp65 in the dorsal spinal cord induced by CCI. After administration with Y-27632 (ROCK inhibitor), SB203580 (P38MAPK inhibitor) or PDTC (NF-κB inhibitor), the levels of P2X4 and P2X7 receptors expression in the dorsal spinal cord were lower than those in CCI rats, which imply that the ROCK/P38MAPK pathway and NF-κB activation may contribute to the increased expression of P2X4 and P2X7 receptor. On the other hand, in CCI rats, AM1241 treatment evoked the increased expression of CB2 receptor and miRNA-124, which can be inhibited by intrathecal injection of CB2 receptor antagonist AM630, which indicate that the increased expression of miRNA-124 may be medicated by CB2 receptor activation. In addition, the increased expression of P2X4 and P2X7 receptors in the dorsal spinal cord of CCI rats were inhibited by miRNA-124 agomir. Furthermore, intrathecal injection of miRNA-124 agomir could efficiently inhibit the ROCK/P38MAPK pathway and NF-κB activation in CCI rats. Moreover, AM1241 treatment significantly inhibited the expression of P2X4 and P2X7 receptors, and this suppression is enhanced by pretreatment with miRNA-124 agomir. On the contrast, the inhibitory effect of AM1241 on the expression of P2X4 and P2X7 receptor can be reversed by pretreatment with miRNA-124 antagomir.Conclusions: In CCI rats, intrathecal injection of AM1241 could efficiently induce the increased expression of miRNA-124, while inhibiting the ROCK/P38MAPK pathway and NF-κB activation in dorsal spinal cord. CB2 receptor/miRNA-124 signaling induced the decreased P2X4 and P2X7 receptors expression via inhibit the ROCK/P38MAPK pathway and NF-κB activation.

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Effect of monoacylglycerol lipase inhibition on intestinal permeability in chronic stress model

10.21203/rs.2.23738/v1 ◽

2020 ◽

Author(s):

Jing Wang ◽

Xiaohua Zhang ◽

Chongmei Yang ◽

Shulei Zhao

Keyword(s):

Tight Junction ◽

Chronic Stress ◽

Intestinal Permeability ◽

Cannabinoid Receptor ◽

Fluorescein Isothiocyanate ◽

Control Group ◽

Monoacylglycerol Lipase ◽

Associated Proteins ◽

Cb1 Antagonist ◽

Novel Target

Abstract Background: The endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid, which is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). The present study aimed to explore the effects of inhibition of MAGL on intestinal permeability. Methods: We first tested it in differentiated CaCO2 cells after 21 days’ culture. The rat model of water avoidance stress (WAS) was established, and rats were divided into four groups according to intervention. Rats received intraperitoneal injection (i.p.) of an MAGL inhibitor (JZL184) alone, JZL184 and the cannabinoid receptor 1 (CB1) antagonist (SR141716A), JZL184 and a cannabinoid receptor 2 (CB2) antagonist (AM630) or vehicle alone (control). We analyzed the fluorescein isothiocyanate-dextran (FD4) permeability and 2-AG level. Expression of MAGL and tight-junction-associated proteins were detected by western blot. Results: Compared with the control group, MAGL expression was higher and 2-AG levels lower among WAS rats. Intestinal permeability was increased following administration of JZL184 which occurred due to up-regulation of tight-junction-associated proteins Claudin-1, Claudin-2, Claudin-5 and Occludin.Conclusion: The effects of MAGL inhibition were mediated by CB1, indicating that MAGL may represent a novel target for the treatment of reduced intestinal permeability in the context of chronic stress.

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β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors

Biomedicines ◽

10.3390/biomedicines8060164 ◽

2020 ◽

Vol 8 (6) ◽

pp. 164 ◽

Cited By ~ 2

Author(s):

Giacomo Picciolo ◽

Giovanni Pallio ◽

Domenica Altavilla ◽

Mario Vaccaro ◽

Giacomo Oteri ◽

...

Keyword(s):

Oral Mucositis ◽

Cannabinoid Receptor ◽

Therapeutic Potential ◽

Preclinical Model ◽

Mrna Levels ◽

Innovative Strategies ◽

Inflammatory Phenotype ◽

Cb2 Receptors ◽

Vitro Model

Human gingival fibroblasts (GF) and human oral mucosa epithelial cells (EC) with an inflammatory phenotype represent a valuable experimental paradigm to explore the curative activity of agents to be used in oral mucositis. The role of cannabinoid receptor 2 (CB2) has not yet been investigated in oral mucositis. The aim of this study was to evaluate the therapeutic potential of β-Caryophyllene (BCP), a CB2 agonist, in an in vitro model of oral mucositis. GF and EC were stimulated with LPS (2 µg/mL) alone or in combination with BCP; a group of LPS challenged GF and EC were treated with BCP and AM630, a CB2 antagonist. LPS increased the inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A whereas it decreased the anti-inflammatory cytokine IL-13. The upstream signals were identified in an augmented expression of NF-κB and STAT-3 and in reduced mRNA levels of PPARγ and PGC-1α. BCP blunted the LPS-induced inflammatory phenotype and this effect was reverted by the CB2 antagonist AM630. These results suggest that CB2 receptors are an interesting target to develop innovative strategies for oral mucositis and point out that BCP exerts a marked curative effect in a preclinical model of oral mucositis which deserves to be confirmed in a clinical setting.

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