Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies

Bartholomäus, Ruben; Nicolussi, Simon; Baumann, Alice; Rau, Mark; Simão, Ana Catarina; Gertsch, Jürg; Altmann, Karl‐Heinz

doi:10.1002/cmdc.201900390

Cited by 6 publications

(5 citation statements)

References 26 publications

(38 reference statements)

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“…Thus, the current study represents the first comprehensive SAR analysis of WOBE437‐derived structures. An SAR study around the natural product guineensine, which one of our groups had disclosed as a potent inhibitor of AEA uptake prior to publication of our work on WOBE437 ( 1 ), [14] has recently appeared [15] . While our investigations of WOBE437 analogues so far have not yielded any compounds with an improved inhibitory profile, our SAR data provide important insights into the relevance of individual structural features of WOBE437 ( 1 ) for potent and selective inhibition of AEA uptake.…”

Section: Introductionmentioning

confidence: 85%

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437

et al. 2020

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WOBE437 ((2E,4E)‐N‐(3,4‐dimethoxyphenethyl)dodeca‐2,4‐dienamide, 1) is a natural product‐derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we synthesized almost 80 analogues of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group, and we investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogues was a more potent inhibitor of anandamide uptake than WOBE437 (1). At the same time, a number of WOBE437 variants exhibited potencies in the sub‐100 nM range, with high selectivity over inhibition of the endocannabinoid‐degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1. Interestingly, profound activity differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group. Some of the compounds described here could be interesting departure points for the development of potent endocannabinoid uptake inhibitors with more drug‐like properties.

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Section: Introductionmentioning

confidence: 85%

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437

et al. 2020

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“…Finally, several analogs of guineensine, dehydropipernonaline, pipercide, and pellitorine have been synthesized , and still need to be evaluated for their potential as senolytic or senomodulating molecules.…”

Section: Senomodulating and Anti-aging Properties Of Guineensine Pipe...mentioning

confidence: 99%

“…Finally, several analogs of guineensine, dehydropipernonaline, pipercide, and pellitorine have been synthesized 122,123 and still need to be evaluated for their potential as senolytic or senomodulating molecules. of senotherapies is rapidly evolving and holds promises for the aged population, the major challenges are the heterogeneity of senescence phenotypes that depends on both the targeted tissue, the age and comorbidities, the lack of universal biomarkers, and the difficulties in discriminating senescent from nonsenescent cells.…”

Section: Properties Of Guineensine Pipercide Dehydropipernonaline And...mentioning

confidence: 99%

Amide Alkaloids as Privileged Sources of Senomodulators for Therapeutic Purposes in Age-Related Diseases

Dotou,

L’honoré,

Moumné

et al. 2024

J. Nat. Prod.

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Nature is an important source of bioactive compounds and has continuously made a large contribution to the discovery of new drug leads. Particularly, plant-derived compounds have long been identified as highly interesting in the field of aging research and senescence. Many plants contain bioactive compounds that have the potential to influence cellular processes and provide health benefits. Among them, Piper alkaloids have emerged as interesting candidates in the context of age-related diseases and particularly senescence. These compounds have been shown to display a variety of features, including antioxidant, anti-inflammatory, neuroprotective, and other bioactive properties that may help counteracting the effects of cellular aging processes. In the review, we will put the emphasis on piperlongumine and other related derivatives, which belong to the Piper alkaloids, and whose senomodulating potential has emerged during the last several years. We will also provide a survey on their potential in therapeutic perspectives of age-related diseases.

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“…The pharmacological evidence of indirect cannabimimetic effects strongly suggests that guineensine also targets eCB cellular reuptake in vivo (Reynoso-Moreno et al, 2017). An efficient total synthesis of guineensine was published which may facilitate the provision of this rare natural product for research (Bartholomäus et al, 2019). Another compound in the list of plant-derived natural AEA uptake inhibitors is the N-benzyl-(9Z,12Z)-octadecadieneamide (macamide 7, shown in Table 11), which exhibited a nanomolar IC 50 value for AEA uptake inhibition but also inhibits FAAH at low micromolar concentrations (Hajdu et al, 2014).…”

Section: Preclinical Development Of Selective Ecb Reuptake Inhibitorsmentioning

confidence: 99%

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

et al. 2023

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The cannabis derivative marijuana is the most widely used recreational drug in the Western world, that is consumed by an estimated 83 million individuals (~3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the USA and worldwide. Compelling research evidence and the FDA cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ 9tetrahydrocannabinol (THC) and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS) -made of receptors, metabolic enzymes and transporters -that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, a critical review of our knowledge of the goods and bads of ECS as a therapeutic target are presented, in order to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. Significance Statement -The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like CB 1 R and CB 2 R) and metabolic enzymes (like FAAH and MAGL), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels providing new opportunities to treat patients.

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Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies

Cited by 6 publications

References 26 publications

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437

Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437

Amide Alkaloids as Privileged Sources of Senomodulators for Therapeutic Purposes in Age-Related Diseases

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

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