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ACS Med Chem Lett. 2012 Nov 14;4(1):41-5. doi: 10.1021/ml300235q. eCollection 2013 Jan 10.

Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55.

Author information

1
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
2
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Hittorfstrasse 58-62, D-48149 Münster, Germany.
3
CH-8592 Uttwil , Oberdorfstrasse 14, Switzerland.

Abstract

The bark of Magnolia officinalis is used in Asian traditional medicine for the treatment of anxiety, sleeping disorders, and allergic diseases. We found that the extract and its main bioactive constituents, magnolol and honokiol, can activate cannabinoid (CB) receptors. In cAMP accumulation studies, magnolol behaved as a partial agonist (EC50 = 3.28 μM) with selectivity for the CB2 subtype, while honokiol was less potent showing full agonistic activity at CB1 and antagonistic properties at CB2. We subsequently synthesized the major metabolites of magnolol and found that tetrahydromagnolol (7) was 19-fold more potent than magnolol (EC50 CB2 = 0.170 μM) exhibiting high selectivity versus CB1. Additionally, 7 behaved as an antagonist at GPR55, a CB-related orphan receptor (K B = 13.3 μM, β-arrestin translocation assay). Magnolol and its metabolites may contribute to the biological activities of Magnolia extract via the observed mechanisms of action. Furthermore, the biphenylic compound magnolol provides a simple novel lead structure for the development of agonists for CB receptors and antagonists for the related GPR55.

KEYWORDS:

CB2 receptor agonists; Chinese traditional medicine; Magnolia officinalis; bioactivation; biphenyls; honokiol; magnolia extract; magnolol; magnolol metabolites

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