Fourteen drugs from five different classes of selective estrogen receptor modulators (SERMs) were screened at cannabinoid receptors, with four showing improved binding and selectivity compared to tamoxifen.
Read this if you follow cannabinoid drug discovery research or are interested in how existing drugs might be repurposed for cannabinoid receptor targeting.
Bazedoxifene selectively targets CB2 receptors; ospemifene selectively targets CB1
What the researchers found
Building on the discovery that tamoxifen interacts with cannabinoid receptors, researchers screened 14 drugs from five structurally distinct classes of SERMs to find compounds with even better cannabinoid receptor properties.
Four of five SERM classes bound to cannabinoid receptors. Among the standout findings: ospemifene selectively bound to CB1 receptors, bazedoxifene selectively bound to CB2 receptors, while nafoxidine and raloxifene bound to both non-selectively. All four acted as inverse agonists, reducing baseline receptor activity.
These newer SERMs showed improved pharmacological characteristics compared to tamoxifen, including better receptor affinity and selectivity. The variety of selectivity profiles across different chemical scaffolds gives drug developers multiple options for targeting specific cannabinoid receptor subtypes.
Why it matters
The ability to selectively target CB1 or CB2 receptors is a major goal in cannabinoid drug development. CB2-selective compounds could potentially treat inflammation and pain without psychoactive effects. This study shows that multiple existing drug scaffolds can achieve this selectivity, expanding the toolkit for medicinal chemists.
The numbers in context
Fourteen SERMs from five classes screened. Four of five classes bound to cannabinoid receptors. Inverse agonist IC50 values ranged from nanomolar to low micromolar. Ospemifene was CB1-selective, bazedoxifene was CB2-selective.
How the study worked
Radioligand binding assays screened 14 SERMs at human CB1 and CB2 receptors. The four most promising compounds underwent full characterization including G-protein activation assays, intracellular cAMP measurements in intact cells, and antagonism studies using concentration-effect curves.
What this study cannot tell us
All data are from cell-based assays. Whether these SERM-derived compounds could be developed into practical cannabinoid drugs remains unknown. The concentrations needed for cannabinoid effects may be higher than typical therapeutic doses for their estrogen-related uses.
How to read the evidence
Systematic cell-based screening with functional validation, but entirely preclinical with no in vivo data.
When this study was published
Published in 2016. Follow-up development of these scaffolds into optimized cannabinoid drugs would require years of additional research.
The bigger picture
This study represents a broadening of the cannabinoid drug discovery pipeline. Rather than relying solely on cannabis-derived or traditional synthetic cannabinoids, researchers can now draw from multiple established drug families to develop new cannabinoid-targeting therapies with potentially fewer side effects.
Questions still open
- Could bazedoxifene's CB2 selectivity be optimized further for anti-inflammatory applications? Do patients taking raloxifene for osteoporosis experience any cannabinoid-mediated effects?
Common questions
Why does CB1 vs CB2 selectivity matter?
Are these drugs being used for cannabinoid purposes now?
Read the original research
Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity.
Frontiers in pharmacology, 7, 503
Citation
Franks, Lirit N; Ford, Benjamin M; Prather, Paul L. (2016). Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity.. Frontiers in pharmacology, 7, 503. https://doi.org/10.3389/fphar.2016.00503
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