Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8538327 | Toxicology and Applied Pharmacology | 2018 | 12 Pages |
Abstract
Selective estrogen receptor modulators (SERMs) target estrogen receptors (ERs) to treat breast cancer and osteoporosis. Several SERMs exhibit anti-cancer activity not related to ERs. To discover novel anti-cancer drugs acting via ER-independent mechanisms, derivatives of the SERM tamoxifen, known as the “ridaifen” compounds, have been developed that exhibit reduced or no ER affinity, while maintaining cytotoxicity. Tamoxifen and other SERMs bind to cannabinoid receptors with moderate affinity. Therefore, ER-independent effects of SERMs might be mediated via cannabinoid receptors. This study determined whether RID-B, a first generation ridaifen compound, exhibits affinity and/or activity at CB1 and/or CB2 cannabinoid receptors. RID-B binds with high affinity (Kiâ¯=â¯43.7â¯nM) and 17-fold selectivity to CB2 over CB1 receptors. RID-B acts as an inverse agonist at CB2 receptors, modulating G-protein and adenylyl cyclase activity with potency values predicted by CB2 affinity. Characteristic of an antagonist, RID-B co-incubation produces a parallel-rightward shift in the concentration-effect curve of CB2 agonist WIN-55,212-2 to inhibit adenylyl cyclase activity. CB2 inverse agonists are reported to exhibit anti-inflammatory and anti-ostoeclastogenic effects. In LPS-activated macrophages, RID-B exhibits anti-inflammatory effects by reducing levels of nitric oxide (NO), IL-6 and IL-1α, but not TNFα. Only reduction of NO concentration by RID-B is mediated by cannabinoid receptors. RID-B also exhibits pronounced anti-osteoclastogenic effects, reducing the number of osteoclasts differentiating from primary bone marrow macrophages in a cannabinoid receptor-dependent manner. In summary, the tamoxifen derivative RID-B, developed with reduced affinity for ERs, is a high affinity selective CB2 inverse agonist with anti-inflammatory and anti-osteoclastogenic properties.
Keywords
WIN-55,212-2SERMCB2RCB1RGPCRTRAPCP-55,940DMEMIBMXG-protein coupled receptorG-protein coupled receptors[35S]GTPγSadenylyl cyclaseAntagonistInverse agonisttartrate-resistant acid phosphataseDulbecco's modification of Eagle's mediumDrug actionChoChinese Hamster OvaryELISAEnzyme-linked immunosorbent assayridSelective estrogen receptor modulatorcannabinoid receptor type 1Estrogen receptorcannabinoid receptorscannabinoid receptor type 2
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Authors
Lirit N. Franks, Benjamin M. Ford, Toshifumi Fujiwara, Haibo Zhao, Paul L. Prather,