Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception
| Autor: | Gustavo Blanco, Jon E. Hawkinson, Kwon Ho Hong, Gladis Sánchez, Shameem Sultana Syeda, Gunda I. Georg |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male endocrine system Ouabain Article 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine In vivo Drug Discovery Testis medicine Animals Humans Na+/K+-ATPase Enzyme Inhibitors Sperm motility Cardiac glycoside 030219 obstetrics & reproductive medicine Sperm flagellum Chemistry Sperm Spermatozoa 3. Good health Isoenzymes 030104 developmental biology Contraception Biochemistry Drug Design Sperm Motility Molecular Medicine Sodium-Potassium-Exchanging ATPase Intracellular medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|