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Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor.
Mol Pharmacol. 2006 Jul; 70(1):41-50.MP

Abstract

Sphingosine-1-phosphate (S1P) and cannabinoid receptors are G-protein-coupled receptors that mediate the effects of S1P and endocannabinoids, respectively. Cannabinoid receptors also mediate the effects of Delta9-tetrahydrocannabinol, the primary psychoactive ingredient in marijuana, whereas S1P receptors contribute to the immunosuppressant effects of 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720). FTY720 is a sphingosine analog that can prevent renal graft rejections and suppress a variety of autoimmune disorders in animal models and clinical trials. We now report that both FTY720 and sphingosine interact with CB1 but not CB2 cannabinoid receptors. FTY720 and sphingosine inhibited the binding of the CB1-selective antagonist [3H]N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide ([3H]SR141716A) and the cannabinoid agonist [3H](-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol ([3H]CP55,940) in a concentration-dependent manner in both CB1-expressing cell lines and mouse cerebellum. However, these compounds did not significantly alter [3H]CP55,940 binding to CB2 receptors. In G-protein activation assays, FTY720 and sphingosine inhibited the maximal stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding by the cannabinoid agonist R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) in a concentration-dependent manner, and this antagonist effect was not mimicked by S1P. FTY720 and sphingosine also inhibited activation of extracellular signal-regulated kinases 1 and 2 and Akt by WIN55,212-2 in intact Chinese hamster ovary (CHO) cells expressing CB1 receptors and attenuated WIN55,212-2-stimulated internalization of a fluorescence-tagged CB1 receptor in CHO cells. Moreover, both FTY720 and sphingosine produced rightward shifts in the concentration-effect curves of cannabinoid agonists for G-protein activation, indicating that they act as competitive CB1 antagonists. These results suggest that the CB1 receptor could be a novel target of FTY720 and that sphingosine could be an endogenous CB11 antagonist.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, 1112 East Clay Street, Box 980524, Richmond, VA 23298, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16571654

Citation

Paugh, Steven W., et al. "Sphingosine and Its Analog, the Immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, Interact With the CB1 Cannabinoid Receptor." Molecular Pharmacology, vol. 70, no. 1, 2006, pp. 41-50.
Paugh SW, Cassidy MP, He H, et al. Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. Mol Pharmacol. 2006;70(1):41-50.
Paugh, S. W., Cassidy, M. P., He, H., Milstien, S., Sim-Selley, L. J., Spiegel, S., & Selley, D. E. (2006). Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. Molecular Pharmacology, 70(1), 41-50.
Paugh SW, et al. Sphingosine and Its Analog, the Immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, Interact With the CB1 Cannabinoid Receptor. Mol Pharmacol. 2006;70(1):41-50. PubMed PMID: 16571654.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. AU - Paugh,Steven W, AU - Cassidy,Michael P, AU - He,Hengjun, AU - Milstien,Sheldon, AU - Sim-Selley,Laura J, AU - Spiegel,Sarah, AU - Selley,Dana E, Y1 - 2006/03/29/ PY - 2006/3/31/pubmed PY - 2006/10/25/medline PY - 2006/3/31/entrez SP - 41 EP - 50 JF - Molecular pharmacology JO - Mol Pharmacol VL - 70 IS - 1 N2 - Sphingosine-1-phosphate (S1P) and cannabinoid receptors are G-protein-coupled receptors that mediate the effects of S1P and endocannabinoids, respectively. Cannabinoid receptors also mediate the effects of Delta9-tetrahydrocannabinol, the primary psychoactive ingredient in marijuana, whereas S1P receptors contribute to the immunosuppressant effects of 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720). FTY720 is a sphingosine analog that can prevent renal graft rejections and suppress a variety of autoimmune disorders in animal models and clinical trials. We now report that both FTY720 and sphingosine interact with CB1 but not CB2 cannabinoid receptors. FTY720 and sphingosine inhibited the binding of the CB1-selective antagonist [3H]N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide ([3H]SR141716A) and the cannabinoid agonist [3H](-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol ([3H]CP55,940) in a concentration-dependent manner in both CB1-expressing cell lines and mouse cerebellum. However, these compounds did not significantly alter [3H]CP55,940 binding to CB2 receptors. In G-protein activation assays, FTY720 and sphingosine inhibited the maximal stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding by the cannabinoid agonist R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) in a concentration-dependent manner, and this antagonist effect was not mimicked by S1P. FTY720 and sphingosine also inhibited activation of extracellular signal-regulated kinases 1 and 2 and Akt by WIN55,212-2 in intact Chinese hamster ovary (CHO) cells expressing CB1 receptors and attenuated WIN55,212-2-stimulated internalization of a fluorescence-tagged CB1 receptor in CHO cells. Moreover, both FTY720 and sphingosine produced rightward shifts in the concentration-effect curves of cannabinoid agonists for G-protein activation, indicating that they act as competitive CB1 antagonists. These results suggest that the CB1 receptor could be a novel target of FTY720 and that sphingosine could be an endogenous CB11 antagonist. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16571654/Sphingosine_and_its_analog_the_immunosuppressant_2_amino_2__2_[4_octylphenyl]ethyl__13_propanediol_interact_with_the_CB1_cannabinoid_receptor_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16571654 DB - PRIME DP - Unbound Medicine ER -