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J. Biol. Chem., Vol. 281, Issue 20, 14192-14206, May 19, 2006

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Alkylamides from Echinacea Are a New Class of Cannabinomimetics

CANNABINOID TYPE 2 RECEPTOR-DEPENDENT AND -INDEPENDENT IMMUNOMODULATORY EFFECTS^*

Stefan Raduner, Adriana Majewska, Jian-Zhong Chen, Xiang-Qun Xie, Jacques Hamon^¶, Bernard Faller^¶, Karl-Heinz Altmann, and Jürg Gertsch¹

From the Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland, the Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77204-5037, and ^¶Novartis Institutes for BioMedical Research, Discovery Technologies, 4002 Basel, Switzerland

Alkylamides (alkamides) from Echinacea modulate tumor necrosis factor mRNA expression in human monocytes/macrophages via the cannabinoid type 2 (CB₂) receptor (Gertsch, J., Schoop, R., Kuenzle, U., and Suter, A. (2004) FEBS Lett. 577, 563–569). Here we show that the alkylamides dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1) and dodeca-2E,4E-dienoic acid isobutylamide (A2) bind to the CB₂ receptor more strongly than the endogenous cannabinoids. The K_i values of A1 and A2 (CB₂ 60 nM;CB₁ >1500 nM) were determined by displacement of the synthetic high affinity cannabinoid ligand [³H]CP-55,940. Molecular modeling suggests that alkylamides bind in the solvent-accessible cavity in CB₂, directed by H-bonding and - interactions. In a screen with 49 other pharmacologically relevant receptors, it could be shown that A1 and A2 specifically bind to CB₂ and CB₁. A1 and A2 elevated total intracellular Ca²⁺ in CB₂-positive but not in CB₂-negative promyelocytic HL60 cells, an effect that was inhibited by the CB₂ antagonist SR144528. At 50 nM, A1, A2, and the endogenous cannabinoid anandamide (CB₂ K_i >200 nM) up-regulated constitutive interleukin (IL)-6 expression in human whole blood in a seemingly CB₂-dependent manner. A1, A2, anandamide, the CB₂ antagonist SR144528 (K_i <10 nM), and also the non-CB₂-binding alkylamide undeca-2E-ene,8,10-diynoic acid isobutylamide all significantly inhibited lipopolysaccharide-induced tumor necrosis factor , IL-1, and IL-12p70 expression (5–500 nM) in a CB₂-independent manner. Alkylamides and anandamide also showed weak differential effects on anti-CD3-versus anti-CD28-stimulated cytokine expression in human whole blood. Overall, alkylamides, anandamide, and SR144528 potently inhibited lipopolysaccharide-induced inflammation in human whole blood and exerted modulatory effects on cytokine expression, but these effects are not exclusively related to CB₂ binding.

Received for publication, February 3, 2006 , and in revised form, March 13, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed. Tel.: 41-44-633-7374; Fax: 41-44-633-1366; E-mail: juerg.gertsch{at}pharma.ethz.ch.

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