Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine.
Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine.
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DOI：
10.1021/acs.jnatprod.8b00062
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发表时间：
2018-04-27
影响因子：
5.1
通讯作者：
Panter KE
中科院分区：
文献类型：
--
作者：
Fitch RW;Snider BB;Zhou Q;Foxman BM;Pandya AA;Yakel JL;Olson TT;Al-Muhtasib N;Xiao Y;Welch KD;Panter KE
在同一种毒蛙（Epipedobates anthonyi）中发现了已知的烟碱乙酰胆碱受体激动剂epibatidine的刚性同系物--阿替米定。天然phantasmidine被发现是一个4：1的比例混合物，丰富的（2aR，4aS，9aS）对映异构体的手性相LC-MS比较的合成对映异构体，其绝对配置先前建立的Mosher的酰胺分析。主要对映异构体在苄基碳上具有与天然地棘蛙素相反的S构型，天然地棘蛙素的苄基碳是R。合成的外消旋体和分离的对映异构体的药理学表征确定，在大多数受试受体中，幻他脒的效力比地棘蛙素低约10倍，但比尼古丁高约100倍。与地棘蛙素不同，幻他脒在其活性方面具有明显的对映选择性，并且其苄基碳具有4aS构型的主要天然对映异构体更具活性。幻他脒的立体选择性药理学归因于其刚性和不对称的形状相比，几乎对称的构象先前建议的地棘蛙素对映体。虽然phantasmidine本身毒性太大，不能直接用于治疗，但我们认为它是一个有用的平台，可用于开发可能具有药理学工具价值的强效和选择性烟碱激动剂。
Phantasmidine, a rigid congener of the well-known nicotinic acetylcholine receptor agonist epibatidine, is found in the same species of poison frog (Epipedobates anthonyi). Natural phantasmidine was found to be a 4:1 scalemic mixture, enriched in the (2aR,4aS,9aS) enantiomer by chiral-phase LC-MS comparison to the synthetic enantiomers whose absolute configurations were previously established by Mosher’s amide analysis. The major enantiomer has the opposite S configuration at the benzylic carbon to natural epibatidine, whose benzylic carbon is R. Pharmacological characterization of the synthetic racemate and separated enantiomers established that phantasmidine is ~10-fold less potent than epibatidine, but ~100-fold more potent than nicotine in most receptors tested. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity and the major natural enantiomer whose benzylic carbon has the 4aS configuration is more active. The stereoselective pharmacology of phantasmidine is ascribed to its rigid and asymmetric shape as compared to the nearly symmetric conformations previously suggested for epibatidine enantiomers. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists which may have value as pharmacological tools.
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影响因子：
11.4
作者：
Hansen, SB;Sulzenbacher, G;Bourne, Y
通讯作者：
Bourne, Y
影响因子：
4.8
作者：
Drisdel, Renaldo C.;Sharp, Douglas;Green, William N.
通讯作者：
Green, William N.
影响因子：
13.8
作者：
Dineley, Kelly T.;Pandya, Anshul A.;Yakel, Jerrel L.
通讯作者：
Yakel, Jerrel L.
影响因子：
2.9
作者：
Lee, ST;Wildeboer, K;Pfister, JA
通讯作者：
Pfister, JA
DOI：
10.1039/a806255b
发表时间：
1998-12-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2
影响因子：
--
作者：
Campillo, N;Páez, JA;Goya, P
通讯作者：
Goya, P