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具有新型多巴胺/5HT2A受体特征的二苯氮杂䓬化合物及三维定量构效关系分析

Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis.

作者信息

Hamacher Alexandra, Weigt Mathias, Wiese Michael, Hoefgen Barbara, Lehmann Jochen, Kassack Matthias U

机构信息

Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

出版信息

BMC Pharmacol. 2006 Sep 15;6:11. doi: 10.1186/1471-2210-6-11.

DOI:10.1186/1471-2210-6-11
PMID:16978403
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1586004/
Abstract

BACKGROUND

Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D1-D5 and 5HT2A receptors and to assign them to different classes according to their dopamine/5HT2A receptor profile.

RESULTS

Regardless of using affinity data (pKi values at D1-D5 and 5HT2A) or selectivity data (15 log (Ki ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT2A ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of Ki ratios used for principal component analysis from 15 to two (the D1/D2 and D2/5HT2A Ki ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D2-like receptor profile (D2L > D3 > D4.4) than clozapine (D4.4 > D2L > D3). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D1 selectivity.

CONCLUSION

In conclusion, two compounds with a novel dopamine/5HT2A receptor profile, LE404 and LE410, with some differences in their respective D1/D2 receptor affinities including a validated pharmacophore-based 3D-QSAR model for D1 antagonists are presented.

摘要

背景

抗精神病药物根据临床疗效和副作用分为典型和非典型化合物。本研究的目的是在体外对一系列新型氮杂环庚三烯类化合物在人多巴胺D1 - D5和5HT2A受体上进行表征，并根据它们的多巴胺/5HT2A受体谱将它们归类到不同类别。

结果

无论使用亲和力数据（D1 - D5和5HT2A的pKi值）还是选择性数据（15log（Ki比率）），对氮杂环庚三烯类化合物、氟哌啶醇和氯氮平进行主成分分析，均揭示了三组多巴胺/5HT2A配体：1）氟哌啶醇；2）氯氮平加四种氮杂环庚三烯类化合物；3）两种羟基化二苯并氮杂环庚三烯。将用于主成分分析的Ki比率数量从15个减少到两个（D1/D2和D2/5HT2A Ki比率）得到了相同的三组化合物。与氯氮平聚集在同一组中的最有效的二苯并氮杂环庚三烯是非羟基化的LE410，其显示出与氯氮平（D4.4 > D2L > D3）略有不同的D2样受体谱（D2L > D3 > D4.4）。单羟基化二苯并氮杂环庚三烯LE404与氯氮平/LE410以及氟哌啶醇聚集在不同的组中，并显示出增加的D1选择性。

结论

总之，提出了两种具有新型多巴胺/5HT2A受体谱的化合物LE404和LE410，它们在各自的D1/D2受体亲和力上存在一些差异，包括一个经过验证的基于药效团的D1拮抗剂3D - QSAR模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/8e8ab84216e6/1471-2210-6-11-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/f179e29ad4d7/1471-2210-6-11-1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/06d2506d400d/1471-2210-6-11-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/68d9d6051ced/1471-2210-6-11-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/68ebb1ddc6b8/1471-2210-6-11-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/8c9c8886234d/1471-2210-6-11-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/8e8ab84216e6/1471-2210-6-11-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/f179e29ad4d7/1471-2210-6-11-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/41256f7cd00b/1471-2210-6-11-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/0b123e85b267/1471-2210-6-11-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/d93429421c07/1471-2210-6-11-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/06d2506d400d/1471-2210-6-11-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/68d9d6051ced/1471-2210-6-11-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/68ebb1ddc6b8/1471-2210-6-11-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/8c9c8886234d/1471-2210-6-11-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01c3/1586004/8e8ab84216e6/1471-2210-6-11-9.jpg

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