دورية أكاديمية
The elucidation of species-specific receptor pharmacology: a case study using subtype selective para - and meta -carborane estrogen receptor agonists .
| العنوان: | The elucidation of species-specific receptor pharmacology: a case study using subtype selective para - and meta -carborane estrogen receptor agonists . |
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| المؤلفون: | Adeluola AA; Pharmaceutics and Pharmacology, The Ohio State University, United States., Radomska HS; Pharmaceutics and Pharmacology, The Ohio State University, United States., Wilson TA; The Ohio State University, United States., Kulp SK; Pharmaceutics and Pharmacology, The Ohio State University, United States., Kabat A; Charles River Labs, United States., Helms TH; The Ohio State University, United States., Mayo AK; Pharmaceutics and Pharmacology, The Ohio State University, United States., Montgomery EJ; Pharmaceutics and Pharmacology, The Ohio State University, United States., Thomas J; The Ohio State University, United States., Marcho LM; The Ohio State University, United States., Costa T; Pharmaceutics and Pharmacology, The Ohio State University, United States., Fukuda M; Pharmaceutics and Pharmacology, The Ohio State University, United States., Kang DD; Pharmaceutics and Pharmacology, The Ohio State University, United States., Vibhute S; The Ohio State University, United States., Wang D; Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, United States., Bennett CE; The Ohio State University, United States., Coss CC; Pharmaceutics and Pharmacology, The Ohio State University, United States coss.16@osu.edu. |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Jun 27. Date of Electronic Publication: 2024 Jun 27. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مستخلص: | Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the meta -carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. Significance Statement This study investigates para - and meta -substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states. (© 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.) |
| فهرسة مساهمة: | Keywords: drug development/discovery; endocrine pharmacology; estrogen receptors; estrogens; sex hormones |
| تواريخ الأحداث: | Date Created: 20240627 Latest Revision: 20240627 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/jpet.123.001874 |
| PMID: | 38936980 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.123.001874 |