Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system

Chicca, Andrea; Caprioglio, Diego; Minassi, Alberto; Petrucci, Vanessa; Appendino, Giovanni; Taglialatela-Scafati, Orazio; Gertsch, Jürg (2014). Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system. ACS Chemical Biology, 9(7), pp. 1499-1507. American Chemical Society 10.1021/cb500177c

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Other Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Chicca, Andrea; Petrucci, Vanessa and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1554-8929

Publisher:

American Chemical Society

Language:

English

Submitter:

Kevin Marc Rupp

Date Deposited:

12 May 2015 09:35

Last Modified:

30 Aug 2016 14:16

Publisher DOI:

10.1021/cb500177c

PubMed ID:

24831513

BORIS DOI:

10.7892/boris.68433

URI:

https://boris.unibe.ch/id/eprint/68433

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