Ac-[3- and 4-alkylthioproline31]-CCK4 analogs: synthesis and implications for the CCK-B receptor-bound conformation.
Ac-[3- and 4-alkylthioproline31]-CCK4 analogs: synthesis and implications for the CCK-B receptor-bound conformation.
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Ac-[3- 和 4-烷基硫代脯氨酸 31]-CCK4 类似物：合成及其对 CCK-B 受体结合构象的影响。
DOI：
10.1021/jm00001a019
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发表时间：
1995
影响因子：
7.3
通讯作者：
Marshall,GR
中科院分区：
文献类型：
--
作者：
Kolodziej,SA;Nikiforovich,GV;Skeean,R;Lignon,MF;Martinez,J;Marshall,GR
有报道将Boc-CCKt中的Met31残基(Boc-Trp30-Met31-As32-Phe33-NH2，CCK33编号)替换为3-丙基-L-Pro，得到了一种高效、选择性的CCK-B激动剂。为了进一步探索CCK4受体结合构象中Met31侧链的结构要求，我们合成了几个含有3-和4-(烷硫基)-取代的Pro取代Met31的Ac-CCK*类似物。为此，我们开发了新的合成路线，合成了对映体纯的N-Boc-4-顺式和反式(甲硫基)脯氨酸和外消旋JV-Boc-3-cíS和-GB Rans-[(4-甲基苄基)硫代]脯氨酸。用SPPS将受保护的硫代脯氨酸结合到Ac-CCKj类似物中，并在从固体载体上裂解后用各种亲电剂进行烷基化。结合分析表明，3-(烷硫基)脯氨酸类似物在CCK-B受体上的亲和力高于相应的4-(烷硫基)脯氨酸类似物，而Frans-3-(烷硫基)脯氨酸类似物的亲和力高于相应的CTS-3-(烷硫基)Pro类似物。在顺式和irans-3-(烷硫基)脯氨酸系列中，其效力顺序为Me<；Et；n-Pr。与文献报道的Boc-CCKI[>；Rans-3-丙基-L-Pro31]相比，Ians-3-(n-丙硫基)-L-Pro类似物具有更高的亲和力。比较几种高亲和力Ac-CCKI类似物的低能结构，揭示了一个共同的几何构象，我们认为这是CCK-B受体结合的构象。这个模型显示了分子一侧Trp、Met和Phe的疏水侧链和另一侧Asp的亲水侧链和C端羧胺的基团。
It has been reported that substitution of the Met31 residue in Boc-CCKt (Boc-Trp30-Met31-Asp32-Phe33-NH2, CCK33 numbering) by írans-3-propyl-L-proline yields a highly potentand selective CCK-B agonist. To further explore the structural requirements of the Met31 side chain in the receptor-bound conformation of CCK4, we have synthesized several Ac-CCK* analogs containing substitution of Met31 by 3-and 4-(alkylthio)-substituted proline derivatives. To this end we have developed novelsynthetic routes to enantiomerically pure N-Boc-4-cis-and-trans-(methylthio) prolines and racemic JV-Boc-3-cís and-£ rans-[(4-methylbenzyl) thio] prolines. The protected mercaptoprolines were incorporated into Ac-CCKj analogs using SPPS and were alkylated using various electrophiles following cleavage from the solid support. Binding assays reveal that 3-(alkylthio) prolines analogs have higher affinities at the CCK-B receptor than the corresponding 4-(alkylthio) proline analogs, and that frans-3-(alkylthio) proline analogs had higher affinities than corresponding cts-3-(alkylthio) proline analogs. Within both the cis-and irans-3-(alkylthio) proline series, theorder of potency was found to be Me< Et< n-Pr. The irans-3-(n-propylthio)-L-proline analog demonstrates a higher affinity than that reported for Boc-CCKi [> rans-3-propyl-L-Pro31]. Comparison of thelow-energy structures calculated for several high-affinity Ac-CCKi analogs reveal a common geometry which we propose to be the CCK-B receptor-bound conformation. This model shows grouping of the hydrophobic side chains of Trp, Met, and Phe at one side of the molecule and the hydrophilic side chain of Asp and the C-terminal carboxamide at the other side.