Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity

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• 作者：Barbora Slav铆kov谩 ; Jordi Bujons ; Libor Maty谩拧 ; Miguel Vidal ; Zoila Babot ; Zdena Kri拧tof铆kov谩 ; Cristina Su帽ol ; Alexander Kasal
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2323-2336
• 全文大小：502K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

(25R)-3尾-Hydroxy-5伪-spirostan-12-one (hecogenin) and 11伪-hydroxypregn-4-ene-3,20-dione (11伪-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5尉-pregnanolone (3伪-hydroxy-5伪-pregnan-20-one and 3伪-hydroxy-5尾-pregnan-20-one), the principal neurosteroid acting via 纬-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABA_A receptor. Their biological activity was measured by in vitro test with [³H]flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABA_A receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic鈥揾ydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor.