The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.

Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenyl)phenol), the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB) receptors. We now investigated the structure-activity relationships of (tetrah...

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Autores principales:	Alexander Fuchs, Viktor Rempel, Christa E Müller
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c1793116671740df9aadfcc075109511
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spelling	oai:doaj.org-article:c1793116671740df9aadfcc0751095112021-11-18T08:48:59ZThe natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.1932-620310.1371/journal.pone.0077739https://doaj.org/article/c1793116671740df9aadfcc0751095112013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24204944/?tool=EBIhttps://doaj.org/toc/1932-6203Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenyl)phenol), the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB) receptors. We now investigated the structure-activity relationships of (tetrahydro)magnolol analogs with variations of the alkyl chains and the phenolic groups and could considerably improve potency. Among the most potent compounds were the dual CB1/CB2 full agonist 2-(2-methoxy-5-propyl-phenyl)-4-hexylphenol (61a, K(i) CB1:0.00957 µM; K(i) CB2:0.0238 µM), and the CB2-selective partial agonist 2-(2-hydroxy-5-propylphenyl)-4-pentylphenol (60, K(i) CB1:0.362 µM; K(i ) CB2:0.0371 µM), which showed high selectivity versus GPR18 and GPR55. Compound 61b, an isomer of 61a, was the most potent GPR55 antagonist with an IC50 value of 3.25 µM but was non-selective. The relatively simple structures, which possess no stereocenters, are easily accessible in a four- to five-step synthetic procedure from common starting materials. The central reaction step is the well-elaborated Suzuki-Miyaura cross-coupling reaction, which is suitable for a combinatorial chemistry approach. The scaffold is versatile and may be fine-tuned to obtain a broad range of receptor affinities, selectivities and efficacies.Alexander FuchsViktor RempelChrista E MüllerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e77739 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alexander Fuchs Viktor Rempel Christa E Müller The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
description	Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenyl)phenol), the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB) receptors. We now investigated the structure-activity relationships of (tetrahydro)magnolol analogs with variations of the alkyl chains and the phenolic groups and could considerably improve potency. Among the most potent compounds were the dual CB1/CB2 full agonist 2-(2-methoxy-5-propyl-phenyl)-4-hexylphenol (61a, K(i) CB1:0.00957 µM; K(i) CB2:0.0238 µM), and the CB2-selective partial agonist 2-(2-hydroxy-5-propylphenyl)-4-pentylphenol (60, K(i) CB1:0.362 µM; K(i ) CB2:0.0371 µM), which showed high selectivity versus GPR18 and GPR55. Compound 61b, an isomer of 61a, was the most potent GPR55 antagonist with an IC50 value of 3.25 µM but was non-selective. The relatively simple structures, which possess no stereocenters, are easily accessible in a four- to five-step synthetic procedure from common starting materials. The central reaction step is the well-elaborated Suzuki-Miyaura cross-coupling reaction, which is suitable for a combinatorial chemistry approach. The scaffold is versatile and may be fine-tuned to obtain a broad range of receptor affinities, selectivities and efficacies.
format	article
author	Alexander Fuchs Viktor Rempel Christa E Müller
author_facet	Alexander Fuchs Viktor Rempel Christa E Müller
author_sort	Alexander Fuchs
title	The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
title_short	The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
title_full	The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
title_fullStr	The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
title_full_unstemmed	The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
title_sort	natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/c1793116671740df9aadfcc075109511
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The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.

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