Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2...

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Oncology

Background:

• Selective estrogen receptor modulators (SERMs) treat ER-positive breast cancer and osteoporosis.
• SERMs like tamoxifen show cytotoxic effects in ER-negative cancers via non-estrogenic pathways.
• Tamoxifen binds cannabinoid receptors (CBRs) as an inverse agonist, suggesting a novel drug target.

Purpose of the Study:

• To identify novel SERM scaffolds with improved cannabinoid receptor (CBR) binding and activity.
• To characterize the affinity and inverse agonism of newer SERMs at CBRs.
• To explore SERM scaffolds for developing safe and selective CBR-acting drugs.

Main Methods:

• Screened 14 SERMs from five structural classes for binding to human CBRs.
• Characterized CBR affinity and activity of selected SERMs (ospemifene, bazedoxifene, nafoxidine, raloxifene).
• Assessed inverse agonism and antagonism via G-protein activity and cAMP assays.

Main Results:

• Four of five SERM classes bound to CBRs.
• Ospemifene selectively bound CB1Rs; bazedoxifene bound CB2Rs.
• Nafoxidine and raloxifene bound CB1 and CB2Rs non-selectively.
• All four compounds acted as inverse agonists and antagonists at CB1 and CB2Rs.

Conclusions:

• Newer SERMs demonstrate enhanced affinity and selectivity for CBRs compared to tamoxifen.
• SERM scaffolds offer potential for developing novel, safe, and selective cannabinoid receptor drugs.
• This study highlights the therapeutic potential of SERMs beyond estrogen receptor modulation.