scholarly journals Synthetic Cannabinoid Agonist WIN 55212-2 Targets Proliferation, Angiogenesis, and Apoptosis via MAPK/AKT Signaling in Human Endometriotic Cell Lines and a Murine Model of Endometriosis

2021 ◽  
Vol 3 ◽  
Author(s):  
Harshavardhan Lingegowda ◽  
Jessica E. Miller ◽  
Ryan M. Marks ◽  
Lindsey K. Symons ◽  
Taylor Alward ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Self Medication ◽  
Syngeneic Mouse ◽  
Win 55 ◽  
Pain Stimuli ◽  
Potential Therapeutic Intervention

Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative in vitro and in vivo syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis in vitro, via MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.

scholarly journals GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Stephen P.H. Alexander ◽  
Andrew J. Irving
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Structural Similarity ◽  
Synthetic Cannabinoid ◽  
Receptor Ligands ◽  
Orphan Status ◽  
Endogenous Cannabinoid

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [98]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

scholarly journals In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018

2020 ◽  
Vol 193 ◽  
pp. 172918
Author(s):  
Thomas F. Gamage ◽  
Daniel G. Barrus ◽  
Richard C. Kevin ◽  
David B. Finlay ◽  
Timothy W. Lefever ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Pharmacological Evaluation ◽  
Synthetic Cannabinoid Receptor Agonist

scholarly journals Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Asher L. Brandt ◽  
Tallan Black ◽  
Eunhyun D. Kim ◽  
Riley Burkart ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Synthetic Cannabinoid ◽  
Receptor Subtype ◽  
Service Agency ◽  
Subtype Selectivity ◽  
Insight Into

AbstractThe first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

607 TJ210 (MOR210), a differentiated anti-C5aR antibody for anti-cancer therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A643-A643
Author(s):  
Jane Meng ◽  
Zhengyi Wang ◽  
Wei Cao ◽  
Chan Chen ◽  
Joan Huaqiong Shen ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Synergistic Effect ◽  
Culture System ◽  
Neutrophil Migration ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model ◽  
Binding Epitope

BackgroundExtensive investigations into the tumor microenvironment (TME) have uncovered molecular mechanisms linking aberrant complement activation and cancer progression. Specifically, C5a, as a highly potent chemoattractant, recruits immune suppressive myeloid derived suppressive cells (MDSCs), neutrophils and M2 macrophages into the tumor site and accelerates tumor progression. Blockade of C5a/C5aR (CD88) pathway has been identified as a promising target to control MDSCs and restore tumor-killing ability of T and NK cells. TJ210, in licensed from MorphoSys as MOR210, is a differentiated anti-C5aR monoclonal antibody with a unique binding epitope.MethodsInteraction of TJ210 with C5aR was assessed through binding of the recombinant antigen, Flp-In CHO cells expressing C5aR and primary neutrophils. In vitro blockade of C5a/C5aR pathway was tested by inhibition of CD11b upregulation on granulocytes and monocytes induced by C5a, as well as neutrophil migration towards C5a. The in vitro synergistic effect of TJ210 with anti-PD-1 antibody was assessed in a T cell and differentiated MDSC co-culture system. The in vivo anti-tumor effect was tested in the MC38 syngeneic mouse model, in which mice were treated with a TJ210 mouse surrogate antibody either alone or in combination with an anti-PD-1 antibody.ResultsTJ210 bound to C5aR with high affinity and did not cross-react with other GPCR members including C5L2, ChemR23, FPR1 and C3aR. Unlike the reference antibody, TJ210 specifically interacted with the N-terminus of C5aR but not extracellular loops. TJ210 effectively inhibited CD11b upregulation on granulocytes and monocytes as well as neutrophil migration mediated by C5a. When compared with the reference antibody, TJ210 maintained potent antagonism at high ligand concentrations and over longer duration, properties that might translate into beneficial in vivo effects at pathophysiological conditions. In the in vitro co-culture system, presence of TJ210 and anti-PD-1 antibody enhanced IFN-γ release compared to either single agent, indicating a synergistic effect on T cells. In the in vivo syngeneic mouse model, combination treatment effectively inhibited tumor growth. Immune cell population analysis revealed significant elevation of CD8+ T cells and M1 macrophages compared to mono-treatment.ConclusionsThis series of in vitro and in vivo data demonstrate that TJ210 is a differentiated anti-C5aR antibody with unique binding epitope exhibiting superior anti-tumor potential especially in combination with an anti-PD-1 antibody. These data support further clinical studies of TJ210 in patients with solid tumors.

scholarly journals A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1396
Author(s):  
Andrew M. Brandon ◽  
Lysbeth H. Antonides ◽  
Jennifer Riley ◽  
Ola Epemolu ◽  
Denise A. McKeown ◽  
...  
Keyword(s):  
Illicit Drug ◽  
Cannabinoid Receptor ◽  
Liver Microsomes ◽  
Drug Market ◽  
Synthetic Cannabinoid ◽  
Pharmacokinetic Studies ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.

scholarly journals Manganese Ferrite Nanoparticles Enhance the Sensitivity of Hepa1-6 Hepatocellular Carcinoma to Radiation by Remodeling Tumor Microenvironments

2021 ◽  
Vol 22 (5) ◽  
pp. 2637
Author(s):  
Sung-Won Shin ◽  
Kyungmi Yang ◽  
Miso Lee ◽  
Jiyoung Moon ◽  
Arang Son ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Hepatoma Cell ◽  
Ferrite Nanoparticles ◽  
Hepatoma Cell Line ◽  
Manganese Ferrite ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

Sign in / Sign up

Export Citation Format

Share Document