903-71-9Relevant academic research and scientific papers
Steroidal Antagonists of Progesterone-and Prostaglandin E 1-Induced Activation of the Cation Channel of Sperm
Carlson, Erick J.,Georg, Gunda I.,Hawkinson, Jon E.
supporting information, p. 56 - 67 (2022/01/28)
The cation channel of sperm (CatSper) is the principal entry point for calcium in human spermatozoa and its proper function is essential for successful fertilization. As CatSper is potently activated by progesterone, we evaluated a range of steroids to define the structure-activity relationships for channel activation and found that CatSper is activated by a broad range of steroids with diverse structural modifications. By testing steroids that failed to elicit calcium influx as inhibitors of channel activation, we discovered that medroxyprogesterone acetate, levonorgestrel, and aldosterone inhibited calcium influx produced by progesterone, prostaglandin E1, and the fungal natural product l-sirenin, but these steroidal inhibitors failed to prevent calcium influx in response to elevated K+ and pH. In contrast to these steroid antagonists, we demonstrated for the first time that the T-type calcium channel blocker ML218 acts similarly to mibefradil, blocking CatSper channels activated by both ligands and alkalinization/depolarization. These T-type calcium channel blockers produced an insurmountable blockade of CatSper, whereas the three steroids produced antagonism that was surmountable by increasing concentrations of each activator, indicating that the steroids selectively antagonize ligand-induced activation of CatSper rather than blocking channel function. Both the channel blockers and the steroid antagonists markedly reduced hyperactivated motility of human sperm assessed by computer-aided sperm analysis, consistent with inhibition of CatSper activation. Unlike the channel blockers mibefradil and ML218, which reduced total and progressive motility, medroxyprogesterone acetate, levonorgestrel, and aldosterone had little effect on these motility parameters, indicating that these steroids are selective inhibitors of hyperactivated sperm motility.
Neurosteroid analogues. 10. The effect of methyl group substitution at the C-6 and C-7 positions on the GABA modulatory and anesthetic actions of (3α,5α)- and (3α,5β)-3-hydroxypregnan-20-one
Zeng, Chun-Min,Manion, Brad D.,Benz, Ann,Evers, Alex S.,Zorumski, Charles F.,Mennerick, Steven,Covey, Douglas F.
, p. 3051 - 3059 (2007/10/03)
The planar 5α-reduced steroid (3α,5α)-3-hydroxypregnan- 20-one and the nonplanar 5β-reduced steroid (3α,5β)-3- hydroxypregnan-20-one act at GABAA receptors to induce general anesthesia. The structural features of the binding sites for these anesthetic steroids on GABAA receptors have not been determined. To determine how structural modifications at the steroid C-6 and C-7 positions effect the actions of these anesthetic steroids, an axial or equatorial methyl group was introduced at these positions. The analogues were evaluated (1) in [ 35S]-tert-butylbicyclophosphorothionate binding experiments, (2) in electrophysiological experiments using rat α1β 2γ2L GABAA receptors expressed in Xenopus laevis oocytes, and (3) as tadpole anesthetics. The effects of methyl group substitution in the 5α- and 5β-reduced series of compounds were strikingly similar. In both series, a 6β-Me group gave compounds with actions similar to or greater than those of the parent steroids. A 6α-, 7β- or 7α-Me substituent resulted in reduced potency for inhibition of radioligand binding, GABAA receptor modulation and tadpole anesthesia. Because of the similar effects of methyl group substitution in the two series of compounds and previous results from other studies showing that structural modifications in the steroid D ring/side chain region produce similar effects regardless of the stereochemistry of the A,B-ring fusion, we propose that either the 3α-hydroxyl groups of planar and nonplanar anesthetic steroids hydrogen bond to different amino acids on GABAA receptors or that this critical hydrogen bonding group interacts with membrane lipids instead of the receptor.
