HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples

Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our o...

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Autor principal:	Matthias Hamburger
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2019
Materias:	gabaa receptor herg piper nigrum evodia rutaecarpa piperine dehydroevodiamine hortiamine Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/631e910eb727464a977122ad5cb00f10
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spelling	oai:doaj.org-article:631e910eb727464a977122ad5cb00f102021-11-17T14:21:56ZHPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples1388-02091744-511610.1080/13880209.2019.1606261https://doaj.org/article/631e910eb727464a977122ad5cb00f102019-01-01T00:00:00Zhttp://dx.doi.org/10.1080/13880209.2019.1606261https://doaj.org/toc/1388-0209https://doaj.org/toc/1744-5116Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our own research, how these goals can be achieved. Methods: An in-house technology platform comprising pre-formatted extract libraries in 96-well format, miniaturized tracking of activity in extracts via HPLC-activity profiling, structure elucidation with microprobe NMR, and in vitro and in vivo pharmacological methods were used. Results: Piperine was identified as a new scaffold for allosteric GABAA receptor modulators with in vivo activity that interacts at a benzodiazepine-independent binding site. Selectivity and potency were improved by iterative optimization towards synthetic piperine analogues. Dehydroevodiamine and hortiamine from the traditional Chinese herbal drug Evodiae fructus were identified as potent hERG channel blockers in vitro. The compounds induced torsades de pointes arrhythmia in animal models. Conclusions: The allosteric binding site for piperine analogues remains to be characterized and cardiac risks of herbal drugs need to be further evaluated to ensure consumer safety.Matthias HamburgerTaylor & Francis Grouparticlegabaa receptorhergpiper nigrumevodia rutaecarpapiperinedehydroevodiaminehortiamineTherapeutics. PharmacologyRM1-950ENPharmaceutical Biology, Vol 57, Iss 1, Pp 328-334 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	gabaa receptor herg piper nigrum evodia rutaecarpa piperine dehydroevodiamine hortiamine Therapeutics. Pharmacology RM1-950
spellingShingle	gabaa receptor herg piper nigrum evodia rutaecarpa piperine dehydroevodiamine hortiamine Therapeutics. Pharmacology RM1-950 Matthias Hamburger HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
description	Context: Discovery of pharmacologically active natural products as starting points for drug development remains important and, for reasons of consumer safety, the identification of toxicologically relevant compounds in herbal drugs. Objective: To explain, with the aid of relevant examples from our own research, how these goals can be achieved. Methods: An in-house technology platform comprising pre-formatted extract libraries in 96-well format, miniaturized tracking of activity in extracts via HPLC-activity profiling, structure elucidation with microprobe NMR, and in vitro and in vivo pharmacological methods were used. Results: Piperine was identified as a new scaffold for allosteric GABAA receptor modulators with in vivo activity that interacts at a benzodiazepine-independent binding site. Selectivity and potency were improved by iterative optimization towards synthetic piperine analogues. Dehydroevodiamine and hortiamine from the traditional Chinese herbal drug Evodiae fructus were identified as potent hERG channel blockers in vitro. The compounds induced torsades de pointes arrhythmia in animal models. Conclusions: The allosteric binding site for piperine analogues remains to be characterized and cardiac risks of herbal drugs need to be further evaluated to ensure consumer safety.
format	article
author	Matthias Hamburger
author_facet	Matthias Hamburger
author_sort	Matthias Hamburger
title	HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
title_short	HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
title_full	HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
title_fullStr	HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
title_full_unstemmed	HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
title_sort	hplc-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples
publisher	Taylor & Francis Group
publishDate	2019
url	https://doaj.org/article/631e910eb727464a977122ad5cb00f10
work_keys_str_mv	AT matthiashamburger hplcbasedactivityprofilingforpharmacologicallyandtoxicologicallyrelevantnaturalproductsprinciplesandrecentexamples
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HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products – principles and recent examples

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