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  • br Results and discussion br Conclusions In summary we


    Results and discussion
    Conclusions In summary, we generated analogues of the hit compounds 1–3, studied their structure–activity relationships, and created a series of highly potent GPR55 agonists. The most potent agonists among the series were 17a-b, 17e, 17g and 17l with EC50 values below 10 nM. The hit compounds 1–3 were further modified by varying the sulfonamide moiety and keeping the biphenyl carboxamide moiety intact. Overall, the N-aryl substituted sulfonamides proved to be the most potent compounds. In addition, the N-alkyl substitution was well tolerated as illustrated by the compounds 2–4, 17o and 17p. However, compounds 3 and 4 having small aliphatic sulfonamide moieties were weakly interacting with other endocannabinoid targets. Compound 3 weakly activated CB1 receptor and inhibited FAAH, whereas Boc-MLF australia 4 just weakly inhibited FAAH. All designed analogues 17a-p were selective for GPR55 over the other tested targets. The GPR55 activity of the ligands was evaluated using a β-arrestin screen at a fixed concentration (10 μM) or changes in intracellular calcium levels to generate concentration-response data. The latter responses are predominantly mediated by the Gα12/13 pathway.29 The results generated using these two approaches were generally in good agreement, however modest differences were observed, for example with 1 (119%, EC50 = 11.9 nM) and 3 (103%, EC50 = 76.2 nM) with some which may indicate agonist biased signalling favouring either Gα12/13 or β-arrestin outputs.
    Experimental section
    Acknowledgements This work was supported by the Academy of Finland (decision nos. 128056, 127653 and 139620), Biocenter Finland/DDCB, the National Graduate School of Organic Chemistry and Chemical Biology, and the Carnegie Trust (Scotland). The authors are grateful to Tiina Koivunen, Miia Reponen, Satu Marttila, and Helly Rissanen for technical assistance. The molecular modelling part was developed using the equipment purchased within the project “The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases” within the Operational Program Development of Eastern Poland 2007–2013, Priority Axis I modern Economy, operations I.3 Innovation promotion. The research was partially performed during the postdoctoral fellowship of Agnieszka A. Kaczor at University of Eastern Finland, Kuopio, Finland under Marie Curie fellowship. Calculations were partially performed under a computational grant by Interdisciplinary Center for Mathematical and Computational Modeling (ICM), Warsaw, Poland, grant number G30-18 and under resources and licenses from CSC, Finland.
    Several G protein-coupled receptors (GPCRs) have been identified that might have a role in the pathophysiology associated with obesity . Much research has focussed on the endocannabinoid system, because of its ability to modulate energy balance (reviewed in , ). A putative GPCR associated with the endocannabinoid system is GPR55 . This receptor might have a role in obesity by acting on peripheral metabolically active tissues, although little is known about the cell signalling pathways initiated by this receptor either under normal conditions or in disease. The endocannabinoid system as a pharmacological target for obesity The prevalence of obesity is increasing at epidemic rates worldwide [5]. The endocannabinoid system is a lipid-derived signalling system [2], which is overactive in the obese state 6, 7. The endocannabinoid system comprises at least two types of GPCR: cannabinoid receptor 1 (CB1) [8] and cannabinoid receptor 2 (CB2) [9]. CB1 and CB2 are expressed in several organs throughout the body, where they have been shown to be involved in regulating energy homeostasis [6]. Modulation of these receptors occurs via ligands known as ‘endocannabinoids’, including anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) [2]. The endocannabinoid system is responsible, in part, for the regulation of energy homeostasis, both centrally and peripherally via activation of cell-specific signalling pathways [6].