Abstract
We have shown recently that estrogen receptor (ER) ligands share a diphenyl ethane pharmacophore with Sah 58-035 [3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide], a prototypical inhibitor of the acyl-cholesterolacyl-transferase (ACAT), which enabled us to establish that ER ligands were potent inhibitors of ACAT and blocked the formation of foam cells. In the present study, we have tested whether this structural similarity means that Sah 58-035 is an ER modulator. We report that Sah 58-035 bound to ERα and ERβ with an IC50 of 2.9 and 3.1 μM, respectively. Docking studies using molecular modeling of Sah 58-035 with the X-ray structure of the ER showed that Sah 58-035 fits well into the ligand binding site known for 4-hydroxy-tamoxifen. Despite having high three-dimensional structural similarities with the pure antiestrogen ICI 164,384 [(N-n-butyl-N-methyl-11-[3,17β-di-hydroxyestra-1,3, 5(10)-trien-7α-yl]-undecanamide], we showed that Sah 58-035 is an agonist of ER for transcription and cellular proliferation. These data showed that Sah 58-035 was an estrogen receptor agonist and that the size and the chemical nature of the side chain were critical for agonist versus antagonist activity on ER. This new molecular mechanism of action for Sah 58-035 has to be taken into account in understanding better its pharmacological activities. Moreover, these data give new structural insights into the understanding of agonist versus antagonist activities of ER ligands and also for the conception of new drugs with a dual ACAT inhibition and ER modulation potential and their evaluation in different pathologies where both targets are involved, such as atherosclerosis, Alzheimer's disease, and cancer.
Footnotes
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S.S.-P. is in charge of research for the Centre National de la Recherche Scientifique. This work was supported by the Institut National de la Santé et de la Recherche Médicale, by the French Ministry of Education and Research, and by grants from the Institut Claudius Regaud.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.104349.
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ABBREVIATIONS: ACAT, acyl-cholesterol-acyl-transferase; Sah 58-035, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide; ER, estrogen receptor; DPE, diphenylethane; DES, diethylstilbestrol; E2, 17β-estradiol; LBD, ligand binding domain; ICI 164,384, (N-n-butyl-N-methyl-11-[3,17β-di-hydroxyestra-1,3,5(10)-trien-7α-yl]-undecanamide; 447C88, (N-heptyl-N′-(2,4 difluoro-4,6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl) urea); TMP-153, N-[4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl]-N′-(2,4-difluorophenyl)urea; PBPE, 1-2-(4-benzylphenoxy)-ethyl]-N-pyrrolidine hydrochloride; R1881, 17-methyltrienolone; PBS, phosphate-buffered saline; AEBS, antiestrogen binding site; OHT, 4-hydroxy-tamoxifen; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; AR, androgen receptor; PR, progesterone receptor; tk, thymidine kinase; SERM, selective estrogen receptor modulator; ICI 182,780, fulvestran; ICI 160,325, N-n-butyl-11-[3,17-di-hydroxyestra-1,3,5(10)-trien-7-yl]-undecanamide; EM-319, N-n-butyl-N-methyl-11-[3,17-di-hydroxy-16-chloro-estra-1,3,5(10)-trien-7-yl)-undecanamide; ZK-164,015, 5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylsulfonyl)decyl]indole; CVFF, consistent valence force field.
- Received March 10, 2006.
- Accepted July 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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