Abstract
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.
Highlights
Cannabinoid receptors (CBRs) are seven-transmembrane spanning G-protein coupled receptors that occur as two subtypes sharing little homology, cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R) [1]
Potential therapeutic uses for drugs acting via CBRs have been sought for decades, drug development in this area has been significantly limited by potential abuse liability and psychotropic effects produced by activation of CB1 receptors in the CNS by compounds such as Δ9-tetrahydrocannabinol (Δ9-THC) present in marijuana (Cannabis sativa) and synthetic cannabinoids found in the emerging drugs of abuse known as K2 and spice [6, 7]
Concerning CBR-selectivity of binding, both E- and Z-Tam bound with significantly higher affinity to hCB2Rs relative to hCB1Rs, with respective selectivity ratios of 1.78 (P
Summary
Cannabinoid receptors (CBRs) are seven-transmembrane spanning G-protein coupled receptors that occur as two subtypes sharing little homology, cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R) [1]. Potential therapeutic uses for drugs acting via CBRs have been sought for decades, drug development in this area has been significantly limited by potential abuse liability and psychotropic effects produced by activation of CB1 receptors in the CNS by compounds such as Δ9-tetrahydrocannabinol (Δ9-THC) present in marijuana (Cannabis sativa) and synthetic cannabinoids found in the emerging drugs of abuse known as K2 and spice [6, 7] Despite such potential adverse effects, CBRs remain therapeutic targets for development of drugs to treat a diverse range of diseases including cancer, obesity, chronic pain, alcohol abuse, osteoporosis, nausea and peripheral tissue injury [7,8,9,10,11]
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