Identification of raloxifene as a novel CB2 inverse agonist

Kumar, Pritesh; Song, Zhao-Hui

doi:10.1016/j.bbrc.2013.04.040

Cited by 27 publications

(27 citation statements)

References 17 publications

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“…17-β-Estradiol could be assumed to increase the expression of CB-2 receptors, as has been previously observed in osteoclasts in vitro (24), or it is possible that estrogens act through other, non-genomic mechanisms (26). Recent studies also show that selective estrogen modulators, raloxifene (27), bazedoxifene and lasofoxifene, behave as CB-2 inverse agonists (28), which may also be true for 17-β-estradiol and would correlate with the present results.…”

Section: Discussionsupporting

confidence: 87%

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

et al. 2015

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Abstract. The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression. In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB). HOB cells were cultured in phenol red-free osteoblast growth medium (37˚C, 5% CO 2 ). In their 5th passage, HOB were exposed to different concentrations of i) 17-β-estradiol (1, 10 and 100 nM); ii) a specific CB-2 agonist (R,S)-AM1241 (1 and 7.5 µM); and iii) a specific CB-2 antagonist/inverse agonist AM630 (10 µM) and to selected combinations of the substances. After 24 and 48 h of incubation, HOB proliferation activity was measured using a WST-8 assay. Alkaline phosphatase activity was also evaluated using spectrophotometry. Concomitant exposure of HOB to 17-β-estradiol (10 nM) and to specific CB-2 antagonist/inverse agonist (10 µM) showed similar HOB proliferation activity to HOB incubated with 17-β-estradiol only at a 100 nM concentration. By contrast, concomitant incubation of HOB with 17-β-estradiol (10 nM) and specific CB-2 agonist (7.5 µM) resulted in decreased HOB proliferation activity as compared to HOB incubated with 17-β-estradiol only (10 nM). Similar findings were observed after 24 and 48 h of incubation. In all the experiments, HOB successfully passed the alkaline phosphatase differentiation test. In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB. Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.

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Section: Discussionsupporting

confidence: 87%

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

et al. 2015

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“…Previously, in an attempt to rapidly and efficiently identify drugs that may act as agonists or inverse agonists for CB2, we screened a library of 640 FDA-approved drugs using a validated high throughput cAMP assay [15]. Our efforts resulted in the identification of raloxifene (Evista), a second generation SERM, as a novel CB2 inverse agonist [15].…”

Section: Introductionmentioning

confidence: 99%

“…Our efforts resulted in the identification of raloxifene (Evista), a second generation SERM, as a novel CB2 inverse agonist [15]. …”

Section: Introductionmentioning

confidence: 99%

CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene

Kumar

Song

2014

Biochemical and Biophysical Research Communications

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The purpose of the current study was to investigate the ability of the third-generation selective estrogen receptor modulators (SERMs) bazedoxifene and lasofoxifene to bind and act on CB2 cannabinoid receptor. We have identified, for the first time, that CB2 is a novel target for bazedoxifene and lasofoxifene. Our results showed that bazedoxifene and lasofoxifene were able to compete for specific [3H]CP-55,940 binding to CB2 in a concentration-dependent manner. Our data also demonstrated that by acting on CB2, bazedoxifene and lasofoxifene concentration-dependently enhanced forskolin-stimulated cAMP accumulation. Furthermore, bazedoxifene and lasofoxifene caused parallel, rightward shifts of the CP-55,940, HU-210, and WIN55,212-2 concentration-response curves without altering the efficacy of these cannabinoid agonists on CB2, which indicates that bazedoxifene- and lasofoxifene-induced CB2 antagonism is most likely competitive in nature. Our discovery that CB2 is a novel target for bazedoxifene and lasofoxifene suggests that these third-generation SERMs can potentially be repurposed for novel therapeutic indications for which CB2 is a target. In addition, identifying bazedoxifene and lasofoxifene as CB2 inverse agonists also provides important novel mechanisms of actions to explain the known therapeutic effects of these SERMs.

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“…The HTRF cAMP assay was performed as previously published [13]. In brief, GPR12 HEK293 cells were washed twice with phosphate-buffered saline (8.1 mM NaH 2 PO 4 , 1.5 mM KH 2 PO 4 , 138 mM NaCl, and 2.7 mM KCl, pH 7.2), and then dissociated in phosphate-buffered saline containing 1 mM EDTA.…”

Section: Methodsmentioning

confidence: 99%

Cannabidiol, a novel inverse agonist for GPR12

Brown

Laun

Song

2017

Biochemical and Biophysical Research Communications

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GPR12 is a constitutively active, Gs protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks Gs protein and pertussis toxin, which blocks Gi protein, revealed that Gs, but not Gi is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis.

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Identification of raloxifene as a novel CB2 inverse agonist

Cited by 27 publications

References 17 publications

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene

Cannabidiol, a novel inverse agonist for GPR12

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