Hogenkamp D J, Tahir S H, Hawkinson J E, Upasani R B, Alauddin M, Kimbrough C L, Acosta-Burruel M, Whittemore E R, Woodward R M, Lan N C, Gee K W, Bolger M B
CoCensys, Inc., Irvine, California 92618, USA.
J Med Chem. 1997 Jan 3;40(1):61-72. doi: 10.1021/jm960021x.
Two naturally occurring metabolites of progesterone, 3 alpha-hydroxy-5 alpha- and 5 beta-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABAA receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3 beta-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5 alpha- and 5 beta-series as determined by inhibition of [35S]TBPS binding. In the 5 alpha-series, 3 beta-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3 beta-XCH2, where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [35S]TBPS binding. In the 5 beta-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3 beta-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5 beta-sterols tested are full inhibitors of [35S]TBPS binding. Electrophysiological measurements using alpha 1 beta 2 gamma 2L receptors expressed in oocytes show that 3 beta-methyl- and 3 beta-(azidomethyl)-3 alpha-hydroxy-5 alpha-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3 alpha-hydroxy-3 beta-(trifluoromethyl)-5 alpha-pregnan -20-one (24) is a low-efficacy modulator, confirming the results obtained from [35S]TBPS binding. These results indicate that modification of the 3 beta-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABAA receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites 1 and 2 are inactive when administered orally, suggesting that 3 beta-substitution slows metabolism of the 3-hydroxyl, resulting in orally bioavailable steroid modulators of the GABAA receptor.
孕酮的两种天然代谢产物，3α-羟基-5α-和5β-孕烷-20-酮（1和2），是GABAA受体的强效变构调节剂。它们作为抗焦虑药、抗惊厥药和镇静/催眠药的治疗潜力受到快速代谢的限制。为避免这些缺点，制备了一系列1和2的3β-取代衍生物。通过抑制[35S]TBPS结合测定，小的亲脂性基团通常在5α-和5β-系列中均保持效力。在5α-系列中，3β-乙基、-丙基、-三氟甲基和-(苄氧基)甲基，以及3β-XCH2形式的取代基（其中X为Cl、Br或I或含有不饱和键），在抑制[35S]TBPS结合方面显示出有限的效力。在5β-系列中，未取代的母体2是一种双组分抑制剂，而2的所有3β-取代衍生物均通过一类结合位点抑制TBPS。此外，所测试的所有3-取代5β-甾醇都是[35S]TBPS结合的完全抑制剂。使用卵母细胞中表达的α1β2γ2L受体进行的电生理测量表明，3β-甲基-和3β-(叠氮甲基)-3α-羟基-5α-孕烷-20-酮（分别为6和22）是强效的完全效能调节剂，而3α-羟基-3β-(三氟甲基)-5α-孕烷-20-酮（24）是低效能调节剂，这证实了从[35S]TBPS结合获得的结果。这些结果表明，1和2中3β-位的修饰在GABAA受体的神经活性甾体位点上维持活性。在动物研究中，化合物6（CCD 1042）是一种口服活性抗惊厥药，而天然存在的孕酮代谢产物1和2口服给药时无活性，这表明3β-取代减缓了3-羟基的代谢，从而产生了GABAA受体的口服生物可利用甾体调节剂。
