<p class="first" id="P1">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
<sub>1</sub> and/or CB
<sub>2</sub> cannabinoid receptors. RID-B binds with high affinity (K
<sub>i</sub> = 43.7 nM) and 17-fold selectivity to CB
<sub>2</sub> over CB
<sub>1</sub> receptors. RID-B acts as an inverse agonist at CB
<sub>2</sub> receptors, modulating G-protein and adenylyl cyclase activity with potency
values
predicted by CB
<sub>2</sub> affinity. Characteristic of an antagonist, RID-B co-incubation produces
a parallel-rightward
shift in the concentration-effect curve of CB
<sub>2</sub> agonist WIN-55,212-2 to inhibit adenylyl cyclase activity. CB
<sub>2</sub> 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
<sub>2</sub> inverse agonist with anti-inflammatory and anti-osteoclastogenic properties.
</p>