Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development

PLoS One. 2016 Dec 9;11(12):e0167240. doi: 10.1371/journal.pone.0167240. eCollection 2016.


Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoid subtype 1 and 2 receptors (CB1R and CB2Rs). Interestingly, cis- (E-Tam) and trans- (Z-Tam) isomers of Tam exhibit over a 100-fold difference in affinity for ERs. Therefore, the current study assessed individual isomers of Tam and subsequent cytochrome P450 metabolic products, 4-hydroxytamoxifen (4OHT) and 4-hydroxy-N-desmethyl tamoxifen (End) for affinity and activity at CBRs. Results showed that Z-4OHT, but not Z-Tam or Z-End, exhibits higher affinity for both CB1 and CB2Rs relative to the E-isomer. Furthermore, Z- and E-isomers of Tam and 4OHT show slightly higher affinity for CB2Rs, while both End isomers are relatively CB1R-selective. When functional activity was assessed by G-protein activation and regulation of the downstream effector adenylyl cyclase, all isomers examined act as full CB1 and CB2R inverse agonists. Interestingly, Z-Tam appears to be more efficacious than the full inverse agonist AM630 at CB2Rs, while both Z-Tam and Z-End exhibit characteristics of insurmountable antagonism at CB1 and CB2Rs, respectively. Collectively, these results suggest that the SERMs Tam, 4OHT and End elicit ER-independent actions via CBRs in an isomer-specific manner. As such, this novel structural scaffold might be used to develop therapeutically useful drugs for treatment of a variety of diseases mediated via CBRs.

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Binding, Competitive
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • CHO Cells
  • Cannabinoid Receptor Agonists / metabolism
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Antagonists / metabolism
  • Cannabinoid Receptor Antagonists / pharmacology
  • Colforsin / metabolism
  • Colforsin / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Cyclohexanols / metabolism
  • Cyclohexanols / pharmacology
  • Female
  • GTP-Binding Proteins / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Indoles / metabolism
  • Indoles / pharmacology
  • Isomerism
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Selective Estrogen Receptor Modulators / chemistry
  • Selective Estrogen Receptor Modulators / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / chemistry
  • Tamoxifen / metabolism*
  • Tamoxifen / pharmacology


  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Cyclohexanols
  • Indoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Selective Estrogen Receptor Modulators
  • Tamoxifen
  • afimoxifene
  • Colforsin
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • 4-hydroxy-N-desmethyltamoxifen
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Cyclic AMP
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • iodopravadoline

Grant support

These studies were supported by bridging funds provided by the UAMS Department of Pharmacology and Toxicology—Dr. Paul L. Prather.