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Functionalization of β-Caryophyllene Generates Novel Polypharmacology in the Endocannabinoid System

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Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Largo Donegani 2, 28100 Novara, Italy
§ Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy
Cite this: ACS Chem. Biol. 2014, 9, 7, 1499–1507
Publication Date (Web):May 5, 2014
https://doi.org/10.1021/cb500177c
Copyright © 2014 American Chemical Society

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    Abstract

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    The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (1) is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure–activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB2 receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of 1. While most changes on this element were detrimental for activity, ring-opening cross metathesis of 1 with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (11a, 11b, 11c) that not only retained the CB2 receptor functional agonism of 1 but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors 11e and 11f, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs.

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