Discovery and Characterization of Multiple Classes of Human CatSper Blockers.
Discovery and Characterization of Multiple Classes of Human CatSper Blockers.
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多种人类CatSper阻断剂的发现和表征。
DOI：
10.1002/cmdc.202000499
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发表时间：
2022-08-03
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
精子的阳离子通道(CatSper)是非激素男性避孕的有效靶点，但它缺乏选择性阻滞剂，阻碍了确定其在运动和获能中的作用的研究。通过利用人类精子的创新钙摄取试验，我们从72,000种化合物的高通量筛选活动中发现了CatSper功能的新抑制剂。七部热门系列剧初步建立了搜救机制。HTS HITS或其更强大的类似物可阻断钾诱导的去极化，并非竞争性地抑制黄体酮诱导的CatSper激活。膜片钳电生理证实CatSper通道被阻断，这些化合物可抑制黄体酮和前列腺素E_1诱导的精子运动亢进。其中一种Hit化合物是一种有效的CatSper抑制剂，其对CatSper的选择性高于hCav1.2，hNav1.5，对hSlo3和Herg的选择性中等，且细胞毒性低，因此是本研究中确定的最有希望的抑制剂。这些新的CatSper阻滞剂是化学探针开发和药物发现工作的有用起点。高通量筛选确定了七个热门系列作为精子阳离子通道(CatSper)的新抑制剂，CatSper是一种有效的男性避孕目标。膜片钳电生理证实CatSper通道被阻断。最有希望的类似物是一种有效的CatSper抑制剂，其对CatSper的选择性高于hCav1.2和hNav1.5，对hSlo3和Herg的选择性中等，且细胞毒性低。
The cation channel of sperm (CatSper) is a validated target for nonhormonal male contraception, but it lacks selective blockers, hindering studies to establish its role in both motility and capacitation. Via an innovative calcium uptake assay utilizing human sperm we discovered novel inhibitors of CatSper function from a high‐throughput screening campaign of 72,000 compounds. Preliminary SAR was established for seven hit series. HTS hits or their more potent analogs blocked potassium‐induced depolarization and noncompetitively inhibited progesterone‐induced CatSper activation. CatSper channel blockade was confirmed by patch clamp electrophysiology and these compounds inhibited progesterone‐ and prostaglandin E1‐induced hyperactivated sperm motility. One of the hit compounds is a potent CatSper inhibitor with high selectivity for CatSper over hCav1.2, hNav1.5, moderate selectivity over hSlo3 and hERG, and low cytotoxicity and is therefore the most promising inhibitor identified in this study. These new CatSper blockers serve as useful starting points for chemical probe development and drug discovery efforts. High‐throughput screening identified seven hit series as novel inhibitors of the cation channel of sperm (CatSper), a validated male contraceptive target. CatSper channel blockade was confirmed by patch clamp electrophysiology. The most promising analog was found to be a potent CatSper inhibitor with high selectivity for CatSper over hCav1.2, hNav1.5, moderate selectivity over hSlo3 and hERG, and low cytotoxicity.
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DOI：
10.1124/jpet.103.060814
发表时间：
2004-04-01
影响因子：
3.5
作者：
Huang, LP;Keyser, BM;Li, M
通讯作者：
Li, M
影响因子：
11.4
作者：
Brenker, Christoph;Goodwin, Normann;Struenker, Timo
通讯作者：
Struenker, Timo
影响因子：
16.6
作者：
Chung JJ;Navarro B;Krapivinsky G;Krapivinsky L;Clapham DE
通讯作者：
Clapham DE
DOI：
10.1530/acta.0.1080407
发表时间：
1985-01-01
期刊：
ACTA ENDOCRINOLOGICA
影响因子：
--
作者：
HILLENSJO, T;SJOGREN, A;ANDINO, N
通讯作者：
ANDINO, N
影响因子：
3.7
作者：
Carlson AE;Burnett LA;del Camino D;Quill TA;Hille B;Chong JA;Moran MM;Babcock DF
通讯作者：
Babcock DF