Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB<sup>1</sup> receptors on peripheral sympathetic nerves

Ishac, Edward J. N.; Liu, Jiang; Lake, Kristy D.; Varga, K; Abood, Mary E.; Kunos, George

doi:10.1111/j.1476-5381.1996.tb15639.x

Cited by 313 publications

(233 citation statements)

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“…Melting points (mp) were determined in open capillaries using a Gallenkamp melting point apparatus and are uncorrected. Nuclear magnetic resonance ( 1 H NMR and 13 C NMR) spectra were recorded on a Bruker Avance DPX 400 spectrometer operating at 400 MHz for 1 H and 100 MHz for 13 C. Chemical shifts are reported in ppm on the δ scale from an internal standard of residual solvent (CDCl 3 7.26 and 77.0 ppm; DMSO-d 6 2.50 and 39.52 ppm). Coupling constants (J) are reported in Hz.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

et al. 2007

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Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC 50 ) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.

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Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

et al. 2007

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“…The in vivo cardiovascular effects of cannabinoids are complex and may comprise direct effects on the myocardium (Bonz et al, 2003) and vasculature (Gebremedhin et al, 1999;Járai et al, 1999;Wagner et al, 2001b), as well as modulation of autonomic outflow in the central (Niederhoffer and Szabo, 2000) and the peripheral nervous systems (Ishac et al, 1996;Malinowska et al, 1997). CB 1 receptors are present in the myocardium where they mediate negative inotropy (Bonz et al, 2003;Pacher et al, 2004) and also in the vasculature (Gebremedhin et al, 1999;Liu et al, 2000), where they lead to vasodilation (Gebremedhin et al, 1999), and both of these sites are implicated in the hypotensive effect of anandamide (Wagner et al, 2001b;Pacher et al, 2004).…”

Section: Cardiovascular Effects Of Cannabinoids In Vivo Role Of Cb 1mentioning

confidence: 99%

“…The cardiovascular depressor effects of anandamide are devoid of a centrally mediated component , although some synthetic cannabinoids can cause centrally mediated sympathoexcitatory effects (Niederhoffer and Szabo, 2000). Presynaptic CB 1 are also present in sympathetic nerve terminals where their stimulation inhibits norepinephrine release (Ishac et al, 1996) contributing to the bradycardic effects of anandamide (Wagner et al, 2001b).…”

Section: Cardiovascular Effects Of Cannabinoids In Vivo Role Of Cb 1mentioning

confidence: 99%

Blood pressure regulation by endocannabinoids and their receptors

2005

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Cannabinoids and their endogenous and synthetic analogs exert powerful hypotensive and cardiodepressor effects by complex mechanisms involving direct and indirect effects on myocardium and vasculature. On the one hand, endocannabinoids and cannabinoid receptors have been implicated in the hypotensive state associated with hemorrhagic, endotoxic and cardiogenic shock, and advanced liver cirrhosis. On the other hand, there is emerging evidence suggesting that the endocannabinergic system plays an important role in the cardiovascular regulation in hypertension. This review is aimed to discuss the in vivo hypotensive and cardiodepressant effects of cannabinoids mediated by cannabinoid and TRPV 1 receptors, and focuses on the novel therapeutical strategies offered by targeting the endocannabinoid system in the treatment of hypertension.

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“…1 Two receptors have been identified by molecular cloning that can recognize cannabinoids with high affinity: the CB1 receptor is present primarily in the brain 2 but also in some peripheral tissues 3,4 and the CB2 receptor is expressed by cells of the immune system. 5 The mRNA of a splice variant of the CB1 receptor, CB1A, has also been identified.…”

mentioning

confidence: 99%

“…7,15,16 Plant-derived cannabinoids can produce cardiovascular effects, including hypotension, 17 that also can be elicited by anandamide 18 -20 and 2-AG. 16 Although at first the hypotensive effect of THC was thought to result from centrally mediated sympathoinhibition, 17 more recent evidence implicates peripheral sites of action, such as receptors located on sympathetic nerve terminals, 4,19,21 receptors located in vascular tissue, or both. 16,20,22 In a recent study, the hypotensive potency of cannabinoid agonists, including anandamide, showed a strong positive correlation with the binding affinity of the same ligands to the brain cannabinoid receptor.…”

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confidence: 99%

Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors

et al. 1999

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Abstract-Cannabinoids, including the endogenous ligand anandamide (arachidonyl ethanolamide), elicit pronounced hypotension in rats via activation of peripherally located CB1 cannabinoid receptors, which have been also implicated in endotoxin (lipopolysaccharide [LPS])-induced hypotension. The present study was designed to test the role of vascular CB1 receptors in cannabinoid-and endotoxin-induced mesenteric vasodilation. In the isolated, buffer-perfused rat mesenteric arterial bed precontracted with phenylephrine, anandamide induced long-lasting (up to 60 minutes) dose-dependent vasodilation (ED 50 : 79Ϯ3 nmol; maximal relaxation: 77Ϯ2%), inhibited by 0.5 to 5.0 mol/L of the selective CB1 receptor antagonist SR141716A. Low doses of the calcium ionophore ionomycin also caused mesenteric vasodilation inhibited by SR141716A. The metabolically stable analogue R-methanandamide elicited mesenteric vasodilation (ED 50 : 286Ϯ29 nmol), whereas the potent synthetic CB1 receptor agonists WIN 55212-2 and HU-210 caused no change in vascular tone or only a minor dilator effect not affected by SR141716A, respectively. The endogenous ligand 2-arachidonyl glycerol caused no change in vascular tone, whereas ⌬ 9 -tetrahydrocannabinol and arachidonic acid caused mesenteric vasoconstriction. After endothelial denudation, the dilator response to anandamide was slightly reduced and was no longer inhibited by SR141716A. In preparations from LPS-pretreated rats, SR141716A alone caused a significant and prolonged increase in perfusion pressure, whereas it had no such effect in control preparations perfused in vitro with or without LPS or after endothelial denudation in preparations from rats pretreated with LPS. We conclude that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR141716A-sensitive "anandamide receptor" distinct from CB1 cannabinoid receptors and that activation of such receptors by an endocannabinoid, possibly anandamide, contributes to LPS-induced mesenteric vasodilation in vivo. Key Words: vasodilation Ⅲ cannabinoids Ⅲ anandamide Ⅲ endotoxin E ndogenous cannabinoids (or endocannabinoids) represent a novel class of lipid ligands that share receptor binding sites with plant-derived cannabinoids, such as ⌬ 9 -tetrahydrocannabinol (THC), and that mimic the neurobehavioral effects of the latter. 1 Two receptors have been identified by molecular cloning that can recognize cannabinoids with high affinity: the CB1 receptor is present primarily in the brain 2 but also in some peripheral tissues 3,4 and the CB2 receptor is expressed by cells of the immune system. 5 The mRNA of a splice variant of the CB1 receptor, CB1A, has also been identified. 3 Two endocannabinoids have been characterized in some detail: arachidonyl ethanolamide, or anandamide, 6 and 2-arachidonyl glyceride, or 2-AG. 7,8 Neurons in the brain can synthesize anandamide 9 and 2-AG, 10 and both substances have been shown to influence central neural functions, such as long-term potentiation. 10,11 Peripheral tissues also contain ...

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Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB¹ receptors on peripheral sympathetic nerves

Cited by 313 publications

References 20 publications

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Blood pressure regulation by endocannabinoids and their receptors

Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors

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Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves

Cited by 313 publications

References 20 publications

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Blood pressure regulation by endocannabinoids and their receptors

Mesenteric Vasodilation Mediated by Endothelial Anandamide Receptors

Contact Info

Product

Resources

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Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB¹ receptors on peripheral sympathetic nerves