scholarly journals CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency

2015 ◽  
Vol 112 (28) ◽  
pp. 8774-8779 ◽  
Author(s):  
Reem Smoum ◽  
Saja Baraghithy ◽  
Mukesh Chourasia ◽  
Aviva Breuer ◽  
Naama Mussai ◽  
...  
Keyword(s):  
Bone Loss ◽  
Binding Affinity ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Osteoclast Differentiation ◽  
Protective Mechanism ◽  
Binding Studies ◽  
Age Related ◽  
Comparative Binding ◽  
Biological Potency

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ9-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3–4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [3H]CP55,940 displacement and its effect on [35S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [35S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.

scholarly journals Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

2020 ◽  
Vol 21 (8) ◽  
pp. 2745
Author(s):  
Yukihiro Kohara ◽  
Ryuma Haraguchi ◽  
Riko Kitazawa ◽  
Yuuki Imai ◽  
Sohei Kitazawa
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Signaling Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Age Related ◽  
Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

The type 2 cannabinoid receptor protects against age-related bone loss and ovariectomy induced bone loss by stimulating bone formation

Bone ◽  
2010 ◽  
Vol 47 ◽  
pp. S42-S43
Author(s):  
A. Sophocleous⁎ ◽  
E. Landao-Bassonga ◽  
R. van 't Hof ◽  
S.H. Ralston ◽  
A.I. Idris
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Cannabinoid Receptor ◽  
Age Related

scholarly journals Inhibiting Monoacylglycerol Lipase Suppresses RANKL-Induced Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Hui Liu ◽  
Chuankun Zhou ◽  
Dahu Qi ◽  
Yutong Gao ◽  
Meipeng Zhu ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Cannabinoid Receptors ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Lipolytic Enzyme ◽  
Monoacylglycerol Lipase

Osteoporosis is a common chronic metabolic bone disease characterized by reduced trabecular bone and increased bone fragility. Monoacylglycerol lipase (MAGL) is a lipolytic enzyme to catalyze the hydrolysis of monoglycerides and specifically degrades the 2-arachidonoyl glycerol (2-AG). Previous studies have identified that 2-AG is the mainly source for arachidonic acid and the most abundant endogenous agonist of cannabinoid receptors. Considering the close relationship between inflammatory mediators/cannabinoid receptors and bone metabolism, we speculated that MAGL may play a role in the osteoclast differentiation. In the present study, we found that MAGL protein expression increased during osteoclast differentiation. MAGL knockdown by adenovirus-mediated shRNA in bone marrow-derived macrophages demonstrated the suppressive effects of MAGL on osteoclast formation and bone resorption. In addition, pharmacological inhibition of MAGL by JZL184 suppressed osteoclast differentiation, bone resorption, and osteoclast-specific gene expression. Activation of the Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways was inhibited by JZL184 and deletion of MAGL. Our in vivo study indicated that JZL184 ameliorated bone loss in an ovariectomized mouse model. Furthermore, overexpressing H1 calponin partially alleviated the inhibition caused by JZL184 or MAGL deletion on osteoclastogenesis. Therefore, we conclude that targeting MAGL may be a novel therapeutic strategy for osteoporosis.

scholarly journals Cannabinoid receptor 1 expression is higher in muscle of old vs. young males, and increases upon resistance exercise in older adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sebastiaan Dalle ◽  
Katrien Koppo
Keyword(s):  
Older Adults ◽  
Resistance Exercise ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Muscle Growth ◽  
Cannabinoid System ◽  
Young Males ◽  
Muscle Plasticity ◽  
Age Related ◽  
Muscle Homeostasis

AbstractAged skeletal muscle undergoes metabolic and structural alterations eventually resulting in a loss of muscle strength and mass, i.e. age-related sarcopenia. Therefore, novel targets for muscle growth purposes in elderly are needed. Here, we explored the role of the cannabinoid system in muscle plasticity through the expression of muscle cannabinoid receptors (CBs) in young and old humans. The CB1 expression was higher (+ 25%; p = 0.04) in muscle of old (≥ 65 years) vs. young adults (20–27 years), whereas CB2 was not differently expressed. Furthermore, resistance exercise tended to increase the CB1 (+ 11%; p = 0.055) and CB2 (+ 37%; p = 0.066) expression in muscle of older adults. Interestingly, increases in the expression of CB2 following resistance exercise positively correlated with changes in key mechanisms of muscle homeostasis, such as catabolism (FOXO3a) and regenerative capacity (Pax7, MyoD). This study for the first time shows that CB1 is differentially expressed with aging and that changes in CB2 expression upon resistance exercise training correlate with changes in mediators that play a central role in muscle plasticity. These data confirm earlier work in cells and mice showing that the cannabinoid system might orchestrate muscle growth, which is an incentive to further explore CB-based strategies that might counteract sarcopenia.

Bronchospasmolytic and Adenosine Binding Activity of 8- (Proline / Pyrazole)-Substituted Xanthine Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Sneha Singh ◽  
Madhwi Ojha ◽  
Divya Yadav ◽  
Sonja Kachler ◽  
Karl-Norbert Klotz ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Radioligand Binding ◽  
Binding Activity ◽  
Receptor Subtypes ◽  
Significant Protection ◽  
Binding Studies ◽  
Standard Drug ◽  
Xanthine Derivatives ◽  
Radioligand Binding Studies ◽  
Micromolar Range

Background: ABSTRACT: Background: 8-Phenyltheophylline derivatives exhibit prophylactic effects at a specific dose but do not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance. Methods: Novel series of 8-(proline/pyrazole)-substituted xanthine analogs has been synthesized. The affinity and selectivity of compounds to adenosine receptors have been assessed by radioligand binding studies. The synthesized compounds also showed good bronchospasmolytic properties (increased onset of bronchospasm; decreased duration of jerks) with 100% survival of animals in comparison to the standard drug. Besides, compound 8f & 9f showed good binding affinity in comparison to other synthesized compounds in the micromolar range. Results: The maximum binding affinity of these compounds was observed for A2B receptors, which is ~ 7 or 10 times higher as compared to A1, A2A and A3 receptors. The newly synthesized derivatives 8f, 9a-f, 17g-m, and 18g-m displayed significant protection against histamine aerosol induced bronchospasm in guinea pigs. Conclusion: Newly synthesized proline/pyrazole based xanthines compounds showed a satisfactory binding affinity for adenosine receptor subtypes. Replacement or variation of substituted proline ring with substituted pyrazole scaffold at 8thposition of xanthine moiety resulted in the reduction of adenosine binding affinity and bronchospasmolytic effects.

Molecular Modeling of an Orphan GPR18 Receptor

2019 ◽  
Vol 16 (10) ◽  
pp. 1167-1174 ◽  
Author(s):  
Kamil J. Kuder ◽  
Tadeusz Karcz ◽  
Maria Kaleta ◽  
Katarzyna Kiec-Kononowicz
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Glycine Receptor ◽  
Homology Model ◽  
Orphan Receptor ◽  
Receptor Ligands ◽  
Orphan Receptors ◽  
Inactive Form ◽  
Starting Point ◽  
Endogenous Cannabinoid

Background: : One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: : Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: : Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion:: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Gram-positive bacteria cell wall-derived lipoteichoic acid induces inflammatory alveolar bone loss through prostaglandin E production in osteoblasts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tsukasa Tominari ◽  
Ayumi Sanada ◽  
Ryota Ichimaru ◽  
Chiho Matsumoto ◽  
Michiko Hirata ◽  
...  
Keyword(s):  
Cell Wall ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Osteoclast Differentiation ◽  
Lipoteichoic Acid ◽  
Alveolar Bone Loss ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria

AbstractPeriodontitis is an inflammatory disease associated with severe alveolar bone loss and is dominantly induced by lipopolysaccharide from Gram-negative bacteria; however, the role of Gram-positive bacteria in periodontal bone resorption remains unclear. In this study, we examined the effects of lipoteichoic acid (LTA), a major cell-wall factor of Gram-positive bacteria, on the progression of inflammatory alveolar bone loss in a model of periodontitis. In coculture of mouse primary osteoblasts and bone marrow cells, LTA induced osteoclast differentiation in a dose-dependent manner. LTA enhanced the production of PGE2 accompanying the upregulation of the mRNA expression of mPGES-1, COX-2 and RANKL in osteoblasts. The addition of indomethacin effectively blocked the LTA-induced osteoclast differentiation by suppressing the production of PGE2. Using ex vivo organ cultures of mouse alveolar bone, we found that LTA induced alveolar bone resorption and that this was suppressed by indomethacin. In an experimental model of periodontitis, LTA was locally injected into the mouse lower gingiva, and we clearly detected alveolar bone destruction using 3D-μCT. We herein demonstrate a new concept indicating that Gram-positive bacteria in addition to Gram-negative bacteria are associated with the progression of periodontal bone loss.

Sign in / Sign up

Export Citation Format

Share Document