Synthetic cannabinoids in drug discovery
Florian Mohr
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Florian Mohr, Synthetic cannabinoids in drug discovery (2020), Logos Verlag, Berlin, ISBN: 9783832587079
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Beschreibung / Abstract
The endocannabinoid system represents a highly complex lipid-based (neuro-) transmitter system and can be found in nearly all animals. Since the discovery of the two main cannabinoid receptors CB1 and CB2 in the early '90, intensive research reviled a substantial influence of this system on many physiological and pathophysiological processes. Direct and selective targeting of the system bears a huge potential for the development of novel therapeutic approaches, especially for the treatment of chronical pain, inflammation or other neurological disorders. Therefore, the endocannabinoid system is a promising target in drug development.
In the presented thesis, the design, syntheses and pharmacologic evaluation of substituted coumarins as potential new drug candidates as selective synthetic cannabinoids were investigated. In a combinatorial synthetic approach, several new libraries of new ligands were synthesised and subsequently pharmacological tested.
Additionally, in a second project, novel reversible monoacylglycerol lipase (MAGL) inhibitors have been synthesized and pharmacologically evaluated. Thereby, several important structure-activity relationships for high potency or selectivity were found. Nearly all potencies of the developed inhibitors were determined in the nanomolar regions.
In the presented thesis, the design, syntheses and pharmacologic evaluation of substituted coumarins as potential new drug candidates as selective synthetic cannabinoids were investigated. In a combinatorial synthetic approach, several new libraries of new ligands were synthesised and subsequently pharmacological tested.
Additionally, in a second project, novel reversible monoacylglycerol lipase (MAGL) inhibitors have been synthesized and pharmacologically evaluated. Thereby, several important structure-activity relationships for high potency or selectivity were found. Nearly all potencies of the developed inhibitors were determined in the nanomolar regions.
Inhaltsverzeichnis
- BEGINN
- 1 Introduction
- 1.1 Drug discovery and development
- 1.2 The endocannabinoid system
- 1.3 Coumarins as synthetic cannabinoid ligands
- 1.4 Monoacylglycerol lipase
- 2 Aim and outline
- 3 Results and discussion
- 3.1 Synthetic work on coumarin-based cannabinoids
- 3.2 Pharmacological evaluation of synthetic cannabinoids
- 3.3 Synthesis and evaluation of MAGL inhibitors
- 4 Conclusion and future prospects
- 5 Experimental part
- 5.1 Synthetic work on coumarin-based cannabinoids
- 5.2 Pharmacological evaluation of synthetic cannabinoids
- 5.3 Synthesis and evaluation of MAGL inhibitors
- 6 Appendix
- 6.1 Synthesis strategy dialkylamino moiety
- 6.2 Synthesis strategy dimethylalkyl moiety
- 6.3 Dialkylamino coumarins
- 6.4 Radioligand binding assay
- 6.5 Functional properties
- 6.6 Metabolic stability
- 6.7 List of Abbreviations
- 6.8 Crystallographic data
- 6.9 Curriculum Vitae
- 7 References
- 8 Acknowledgments