The tamoxifen derivative ridaifen-B is a high affinity selective CB ₂ receptor inverse agonist exhibiting anti-inflammatory and anti-osteoclastogenic effects

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 CB ₁ and/or CB ₂ cannabinoid receptors. RID-B binds with high affinity (K _i = 43.7 nM) and 17-fold selectivity to CB ₂ over CB ₁ receptors. RID-B acts as an inverse agonist at CB ₂ receptors, modulating G-protein and adenylyl cyclase activity with potency values predicted by CB ₂ affinity. Characteristic of an antagonist, RID-B co-incubation produces a parallel-rightward shift in the concentration-effect curve of CB ₂ agonist WIN-55,212-2 to inhibit adenylyl cyclase activity. CB ₂ 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 CB ₂ inverse agonist with anti-inflammatory and anti-osteoclastogenic properties.