Design, Synthesis, and Biological Evaluation of New 1,8-Naphthyridin-4(1H)-on-3-carboxamide and Quinolin-4(1H)-on-3-carboxamide Derivatives as CB2Selective Agonists

Manera, Clementina; Benetti, Veronica; Castelli, Paola; Cavallini, Tiziana; Lazzarotti, Sara; Pibiri, Fabio; Saccomanni, Giuseppe; Tuccinardi, Tiziano; Vannacci, Alfredo; Martinelli, Adriano; Ferrarini, Pier Luigi

doi:10.1021/jm0603466

Cited by 66 publications

(59 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The newly synthesized CB 2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) was supplied by C.M. (18). The ceramide synthase inhibitor fumonisin B1 was purchased from Cayman Chemical Co.…”

Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

Cianchi

Papucci²,

Schiavone³

et al. 2008

Clinical Cancer Research

Self Cite

166

136

View full text Add to dashboard Cite

Purpose: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB 1 and CB 2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation. Experimental Design: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB 1 agonist arachinodyl-2'-chloroethylamide and the CB 2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-a production were evaluated. The knockdown of TNF-a mRNA was obtained with the use of selective small interfering RNA. Results: We show that the CB 1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB 2 receptor. The activation of the CB 1 and, more efficiently, of the CB 2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB 2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-a mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation.Conclusions: The present study shows that either CB 1 or CB 2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, thatTNF-a acts as a link between cannabinoid receptor activation and ceramide production.

show abstract

Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

Cianchi

Papucci²,

Schiavone³

et al. 2008

Clinical Cancer Research

Self Cite

166

136

View full text Add to dashboard Cite

show abstract

“…It is interesting to note that recently described 1,8-naphthyridin-4-ones exhibited very good affinity for the CB 2 cannabinoid receptor subtype [67].…”

Section: 8-naphthyridinonesmentioning

confidence: 88%

CB1 Cannabinoid Antagonists: Structure-Activity Relationships and Potential Therapeutic Applications

Jagerovic¹,

Fernandez-Fernandez²,

Goya

2008

CTMC

View full text Add to dashboard Cite

During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.

show abstract

“…Structural changes in THC structure led to the synthesis of selective CB2 agonists, those most frequently used as pharmacological tools are HU-308 [88], a non-classical cannabinoid; JWH-133, a classical cannabinoid; and JWH-015 and AM124, aminoalkylindoles [81, 89]. New series of compounds have been recently described including diarylether sulfonylesters [90], pyrroles with neuro-protective properties [91], naphthyridin and quinolin derivatives [92, 93], which possess immune-modulatory properties [94, 95]. …”

Section: Synthetic Cannabinoidsmentioning

confidence: 99%

What we know and do not know about the cannabinoid receptor 2 (CB2)

Malfitano

Basu

Maresz

et al. 2014

Seminars in Immunology

100

View full text Add to dashboard Cite

It well appreciated that the endocannabinoid system can regulate immune responses via the cannabinoid receptor 2 (CB2), which is primarily expressed by cells of the hematopoietic system. The endocannabinoid system is composed of receptors, ligands and enzymes controlling the synthesis and degradation of endocannabinoids. Along with endocannabinoids, both plant-derived and synthetic cannabinoids have been shown to bind to and signal through CB2 via G proteins leading to both inhibitory and stimulatory signals depending on the biological process. Because no cannabinoid ligand has been identified that only binds to CB2, the generation of mice deficient in CB2 has greatly expanded our knowledge of how CB2 contributes to immune cell development and function in health and disease. In regards to humans, genetic studies have associated CB2 with a variety of human diseases. Here, we review the endocannabinoid system with an emphasis on CB2 and its role in the immune system.

show abstract

Design, Synthesis, and Biological Evaluation of New 1,8-Naphthyridin-4(1H)-on-3-carboxamide and Quinolin-4(1H)-on-3-carboxamide Derivatives as CB₂Selective Agonists

Cited by 66 publications

References 42 publications

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

CB1 Cannabinoid Antagonists: Structure-Activity Relationships and Potential Therapeutic Applications

What we know and do not know about the cannabinoid receptor 2 (CB2)

Contact Info

Product

Resources

About