Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT7AR ligands.
Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT7AR ligands.
复制标题
通过 C10 氮化对阿朴啡进行结构操作，从而鉴定出新的 5-HT7AR 配体。
DOI：
10.1016/j.bmc.2020.115578
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发表时间：
2020
影响因子：
3.5
通讯作者：
Harding,WayneW
中科院分区：
文献类型：
--
作者：
Karki,Anupam;Namballa,HariK;Alberts,Ian;Harding,WayneW
合成了含有C10氮基序的阿朴啡生物碱，并评价了对5-HT 1AR、5-HT 2AR、5-HT 6 R和5-HT 7AR的亲和力。研究了三个系列的外消旋阿朴啡：1，2，10-三取代的、C10 N-单取代的和含有C10苯并稠合氨基噻唑部分的化合物。1，2，10-三取代系列化合物作为一组显示出对5-HT 7AR的适度选择性，并且也具有中等的5-HT 7AR亲和力。来自C10 N-单取代系列的化合物通常对5-HT 2AR和5-HT 6 R缺乏亲和力，而对5-HT 1A或5-HT 7AR显示出强亲和力。在这一系列的化合物中，含有一个N6-甲基基团的5-HT 7AR的选择性高达27倍的5-HT 1AR，而与一个N6-丙基取代基的化合物显示在这种选择性的逆转。C10苯并稠合氨基噻唑类似物显示出与C10 N-单取代系列类似的结合特征，即对5-HT 1AR或5-HT 7AR具有强亲和力，两种受体之间的选择性受到N6-甲基或N6-丙基取代基的类似影响。化合物29和34 a表现出高的5-HT 7 AR亲和力、对多巴胺受体的优异选择性，并且在基于5-HT 7 AR cAMP的测定中作为拮抗剂起作用。化合物29和34 a已被鉴定为用于进一步工具和药物优化的新的先导分子。
Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT1AR, 5-HT2AR, 5-HT6R and 5-HT7AR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT7AR and also had moderate 5-HT7AR affinity. Compounds from the C10N-monosubstituted series generally lacked affinity for 5-HT2AR and 5-HT6R and showed strong affinity for 5-HT1Aor 5-HT7AR. Compounds in this series that contained anN6-methyl group were up to 27-fold selective for 5-HT7AR over 5-HT1AR, whereas compounds with anN6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10N-monosubstituted series i.e. strong affinity for 5-HT1AR or 5-HT7AR, with selectivity between the two receptors being similarly influenced byN6-methyl orN6-propyl substituents. Compounds29and34aexhibit high 5-HT7AR affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT7AR cAMP-based assays. Compounds29and34ahave been identified as new lead molecules for further tool and pharmaceutical optimization.