Functionalization of 尾-Caryophyllene Generates Novel Polypharmacology in the Endocannabinoid System
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- 作者：Andrea Chicca ; Diego Caprioglio ; Alberto Minassi ; Vanessa Petrucci ; Giovanni Appendino ; Orazio Taglialatela-Scafati ; J眉rg Gertsch
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：July 18, 2014
- 年：2014
- 卷：9
- 期：7
- 页码：1499-1507
- 全文大小：458K
- ISSN：1554-8937
文摘
The widespread dietary plant sesquiterpene hydrocarbon 尾-caryophyllene (<b>1b>) is a CBb>2 b> 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鈥揳ctivity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CBb>2 b> receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of <b>1b>. While most changes on this element were detrimental for activity, ring-opening cross metathesis of <b>1b> with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (<b>11ab>, <b>11bb>, <b>11cb>) that not only retained the CBb>2 b> receptor functional agonism of <b>1b> but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and 伪,尾 hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors <b>11eb> and <b>11fb>, 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 <b>1b>, 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.