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5-甲氧基-N,N-二甲基色胺及其相关色胺的吲唑类似物作为5-羟色胺受体2激动剂的评估

Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.

作者信息

Jayakodiarachchi Navoda, Maurer Mallory A, Schultz Daniel C, Dodd Cayden J, Thompson Gray Analisa, Cho Hyekyung P, Boutaud Olivier, Jones Carrie K, Lindsley Craig W, Bender Aaron M

机构信息

Warren Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.

出版信息

ACS Med Chem Lett. 2024 Jan 19;15(2):302-309. doi: 10.1021/acsmedchemlett.3c00566. eCollection 2024 Feb 8.

DOI:10.1021/acsmedchemlett.3c00566
PMID:38352850
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10860182/
Abstract

Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT) agonists. Specifically, we examine the 5-HT pharmacology of the direct indazole analogs of 5-methoxy-,-dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT subtype selectivity for these analogs, particularly for the 5-HT receptor subtype. Within this series, the potent analog VU6067416 () was optimized to have suitable preclinical pharmacokinetic properties for dosing, although potent 5-HT agonist activity precluded further characterization for this series. Additionally, docking studies suggest that the high potency of may be a consequence of a halogen-bonding interaction with Phe234 in the 5-HT orthosteric pocket.

摘要

在此，我们报告了一组新型取代吲唑乙胺和吲唑四氢吡啶作为强效5-羟色胺受体2型（5-HT）激动剂的合成与表征。具体而言，我们研究了5-甲氧基-N,N-二甲基色胺（5-MeO-DMT）及其相关5-羟色胺能色胺的直接吲唑类似物的5-HT药理学，并强调了对这些类似物，特别是对5-HT受体亚型的5-HT亚型选择性进行严格表征的必要性。在该系列中，强效类似物VU6067416（）经过优化，具有适合给药的临床前药代动力学性质，尽管强效5-HT激动剂活性妨碍了对该系列的进一步表征。此外，对接研究表明，的高效能可能是与5-HT正构口袋中的苯丙氨酸234发生卤键相互作用的结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/14b03c909247/ml3c00566_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/95eed73a47a3/ml3c00566_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/115e3558c8c8/ml3c00566_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/4d548ecfb53e/ml3c00566_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/e25467ec89ae/ml3c00566_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/85d15254924d/ml3c00566_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/14b03c909247/ml3c00566_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/95eed73a47a3/ml3c00566_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/115e3558c8c8/ml3c00566_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/4d548ecfb53e/ml3c00566_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/e25467ec89ae/ml3c00566_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/85d15254924d/ml3c00566_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dba3/10860182/14b03c909247/ml3c00566_0002.jpg

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