Marino Silvia, de Ridder Daniëlle, Bishop Ryan T., Renema Nathalie, Ponzetti Marco, Sophocleous Antonia, Capulli Mattia, Aljeffery Abdullah, Carrasco Giovana, Gens Marianela Dalghi, Khogeer Asim, Ralston Stuart H., Gertsch Jürg, Lamoureux Francois, Heymann Dominique, Rucci Nadia, Idris Aymen I. (2019), Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice, in EBioMedicine
, 44, 452-466.
Gertsch Jürg (2019), Scaffold and organism hopping with chemical probes, in Nature Chemical Biology
, 15(5), 428-429.
Granchi Carlotta, Lapillo Margherita, Glasmacher Sandra, Bononi Giulia, Licari Cristina, Poli Giulio, el Boustani Maguie, Caligiuri Isabella, Rizzolio Flavio, Gertsch Jürg, Macchia Marco, Minutolo Filippo, Tuccinardi Tiziano, Chicca Andrea (2019), Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor, in Journal of Medicinal Chemistry
, 62(4), 1932-1958.
Chicca A., Schafroth M. A., Reynoso-Moreno I., Erni R., Petrucci V., Carreira E. M., Gertsch J. (2018), Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high, in Science Advances
, 4(10), eaat2166-eaat2166.
Varga Zoltan V., Matyas Csaba, Erdelyi Katalin, Cinar Resat, Nieri Daniela, Chicca Andrea, Nemeth Balazs Tamas, Paloczi Janos, Lajtos Tamas, Corey Lukas, Hasko Gyorgy, Gao Bin, Kunos George, Gertsch Jürg, Pacher Pal (2018), β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in miceβ-Caryophyllene is hepatoprotective, in British Journal of Pharmacology
, 175(2), 320-334.
Petrucci Vanessa, Chicca Andrea, Glasmacher Sandra, Paloczi Janos, Cao Zongxian, Pacher Pal, Gertsch Jürg (2017), Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage, in Scientific Reports
, 7(1), 9560-9560.
Gachet María Salomé, Schubert Alexandra, Calarco Serafina, Boccard Julien, Gertsch Jürg (2017), Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom, in Scientific Reports
, 7(1), 41177-41177.
Bertini Simone, Chicca Andrea, Gado Francesca, Arena Chiara, Nieri Daniela, Digiacomo Maria, Saccomanni Giuseppe, Zhao Pingwei, Abood Mary E., Macchia Marco, Gertsch Jürg, Manera Clementina (2017), Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor, in Bioorganic & Medicinal Chemistry
, 25(24), 6427-6434.
Chicca Andrea, Berg Regina, Jessen Henning J., Marck Nicolas, Schmid Fabian, Burch Patrick, Gertsch Jürg, Gademann Karl (2017), Biological evaluation of pyridone alkaloids on the endocannabinoid system, in Bioorganic & Medicinal Chemistry
, 25(22), 6102-6114.
Patsenker Eleonora, Chicca Andrea, Petrucci Vanessa, Moghadamrad Sheida, de Gottardi Andrea, Hampe Jochen, Gertsch Jürg, Semmo Nasser, Stickel Felix (2017), 4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice, in Journal of Molecular Medicine
, 95(10), 1077-1089.
Soethoudt Marjolein, Grether Uwe, Fingerle Jürgen, Grim Travis W., Fezza Filomena, de Petrocellis Luciano, Ullmer Christoph, Rothenhäusler Benno, Perret Camille, van Gils Noortje, Finlay David, MacDonald Christa, Chicca Andrea, Gens Marianela Dalghi, Stuart Jordyn, de Vries Henk, Mastrangelo Nicolina, Xia Lizi, Alachouzos Georgios, Baggelaar Marc P., Martella Andrea, Mock Elliot D., Deng Hui, Heitman Laura H., et al. (2017), Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity, in Nature Communications
, 8, 13958-13958.
Gertsch Jürg (2016), Editorial: Lung macrophages high on cannabinoids: jamming PAMs and taming TAMs?, in Journal of Leukocyte Biology
, 99(4), 518-520.
Cannabinoid receptors are G protein-coupled receptors (GPCRs) that are expressed in the CNS (mainly CB1 receptor) and in peripheral tissues, such as immune cells (CB1 and CB2 receptors). They act via Gai/o pathways, depending on the cell type where they are expressed. Both CB1 and CB2 receptors are involved in numerous physiological and pathophysiological conditions and potential drug targets. Modulation of CB1 receptors is implicated in different areas of neurotransmission and inhibition of excitotoxicity, as well as lipid metabolism. Activation of CB2 receptors is a protective mechanism, leading to anti-fibrotic and anti-inflammatory effects in different tissues. CB receptors are activated by arachidonic acid-derived endocannabinoids, such as N-arachidonoylethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG). Recently, a group of endogenous alpha hemoglobin (HBA1/HBA2) derived peptides have been shown to interact with CB1 receptors with high affinity (Kd values in the low nM range) and proposed to be potential endogenous modulators. In the first SNF funded project on the origin and function of peptide endocannabinoids (31003A_141174) we were able generate conclusive receptor pharmacological data on the effects of RVD-hemopressin (here called Pepcan12) on CB1 receptors as a negative allosteric modulator (NAM) (Bauer et al., JBC, 2012) and on CB2 receptors as a positive allosteric modulator (PAM) (yet unpublished). Moreover, we discovered that these peptides are produced exclusively in noradrenergic neurons and in the adrenal medulla (Hofer et al., Neuropharmacology, 2015). Intriguingly, the chromaffin cells of the adrenal medulla exclusively generate Pepcan12 in nmol/mg quantities. In the present project, we will continue our study on the origin and function of this class of peptides (in particular Pepcan12) in the adrenals, with the aim to further elucidate their potential physiological roles mediated via CB receptors in the periphery. Numerous studies have shown that excess activation of CB1 receptors in the periphery can lead to pathophysiological conditions while the widely accepted view is that CB2 activation exerts protective effects. Pepcan12 being a NAM at CB1 receptors and a PAM at CB2 receptors may be a relevant endogenous modulator for the endocannabinoid system (ECS), regulating CB1/CB2 receptor activation under conditions of differential endocannabinoid levels. Given our previous findings we hypothesize that also the sympathetic noradrenergic ganglia produce pepcan12 and that this neuropeptide is released upon stress from the adrenal gland into the blood. Having identified the site of production of these peptides we will now use biochemical tools to elucidate the biosynthesis and degradation of these peptides. Moreover, in collaboration with our in house animal facility and a contract research organization and our collaborator Prof. Beat Lutz (Mainz) we aim to generate mice deficient of the pepcan12 sequence in cells expressing dopamine beta-hydroxylase (DBH) (using DBH Cre mice. Our group will focus on the functional role of peripheral pepcans originating from the adrenal medulla and possible other sources (noradrenergic ganglia and parasympathetic nerves), studying the neuroimmunomodulatory relevance of pepcan12 expression in the presence of endocannabinoids mediated via CB receptors in functional models of endotoxemia and bone homeostasis. In a further subproject, the actual site of action (allosteric binding site) of this peptide at CB1/2 receptors will be identified, as it may be a potential novel target site for small organic molecules. Given our expertise in chemical biology (e.g., Chicca et al., 2014, ACS Chem Biol) we aim to identify small organic molecules that bind to the Pepcan binding site in CB receptors (either blocking or activating) as novel tools to study their physiological relevance.