Anti-inflammatory lipoxin A
            <sub>4</sub>
            is an endogenous allosteric enhancer of CB
            <sub>1</sub>
            cannabinoid receptor

Pamplona, Fabrício A.; Ferreira, Juliano; Lima, Octávio Menezes de; Duarte, Filipe S.; Bento, Allisson Freire; Forner, Stefânia; Villarinho, Jardel Gomes; Bellocchio, Luigi; Wotjak, Carsten T.; Lerner, Robert G.; Monory, Krisztina; Lutz, Beat; Canetti, Cláudio; Matías, Isabelle; Calixto, João B.; Marsicano, Giovanni; Guimarães, Marília Zaluar P.; Takahashi, Reinaldo Ν.

doi:10.1073/pnas.1202906109

Cited by 161 publications

(210 citation statements)

References 52 publications

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“…We next performed functional interaction studies between each putative modulator and the cannabinoids previously shown to be modulated by either pregnenolone or lipoxin A4. In contrast to studies reporting attenuation of D 9 -THCinduced activation of pERK1/2 by pregnenolone in CHO-hCB 1 cells (Vallee et al, 2014), and enhancement of anandamidemediated inhibition of cAMP formation by lipoxin A4 in HEK-CB 1 cells (Pamplona et al, 2012), our results revealed a complete lack of modulation of CB 1 R signaling by these compounds at concentrations up to 10 mM and 500 nM, respectively (Fig. 5).…”

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confidence: 55%

“…These latter compounds are particularly intriguing because they potentiate agonist binding to the CB 1 R, at the same time inhibiting agonist activity in numerous functional assays (Price et al, 2005;Horswill et al, 2007). Other endogenous ligands, including pregnenolone, pepcans, and lipoxin A4, may also act allosterically at CB 1 Rs, as was recently suggested (Bauer et al, 2012;Pamplona et al, 2012;Vallee et al, 2014). However, further studies are required to validate these putative allosteric effects.…”

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confidence: 96%

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Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

et al. 2015

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CB 1 cannabinoid receptors (CB 1 Rs) are attractive therapeutic targets for numerous central nervous system disorders. However, clinical application of cannabinoid ligands has been hampered owing to their adverse on-target effects. Ligand-biased signaling from, and allosteric modulation of, CB 1 Rs offer pharmacological approaches that may enable the development of improved CB 1 R drugs, through modulation of only therapeutically desirable CB 1 R signaling pathways. There is growing evidence that CB 1 Rs are subject to ligand-biased signaling and allosterism. Therefore, in the present study, we quantified ligand-biased signaling and allosteric modulation at CB 1 Rs. Cannabinoid agonists displayed distinct biased signaling profiles at CB 1 Rs. For instance, whereas 2-arachidonylglycerol and WIN55,212-2 [(R)- (1) [5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide] displayed biased allosteric effects by blocking cAMP inhibition mediated by all cannabinoid ligands tested, at the same time having little or no effect on ERK1/2 phosphorylation mediated by a subset of these ligands. Org27569 also displayed negative binding cooperativity with [however, it had minimal effects on binding of cannabinoid agonists. Furthermore, we highlight the need to validate the reported allosteric effects of the endogenous ligands lipoxin A4 and pregnenolone at CB 1 Rs. Pregnenolone but not lipoxin A4 displaced [ 3 H]SR141716A, but there was no functional interaction between either of these ligands and cannabinoid agonists. This study demonstrates an approach to validating and quantifying ligand-biased signaling and allosteric modulation at CB 1 Rs, revealing ligand-biased "fingerprints" that may ultimately allow the development of improved CB 1 R-targeted therapies.

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confidence: 55%

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confidence: 96%

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

et al. 2015

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“…Blockade of AEA uptake by UCM707 abolished hyperkinesia in rodent models of HD and reduced spasticity in MS rats [178]. However, the elevation in AEA could produce psychotropic effects and tolerance upon CB 1 R activation [179], which has not been seen as a side effect of CBD [180]. Therefore, the binding of CBD to the AEA transporter will not provide a therapeutic effect in movement disorders.…”

Section: Cbd Transporter Targets In Movement Disordersmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…This new class of molecules includes the anti-inflammatory lipid lipoxin A4, which, by enhancing AEA-induced CB1 activation, displays a protective effect against ␤-amyloid (1-40)-induced spatial memory impairment in mice (653). Negative modulators are the ␣-hemoglobin-derived small peptide endocannabinoids (or pepcans), and the neurosteroid pregnenolone (51, 867).…”

Section: Endogenous Allosteric Modulators Of Cb1 Receptorsmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

366

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Cited by 161 publications

References 52 publications

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

Molecular Targets of Cannabidiol in Neurological Disorders

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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Anti-inflammatory lipoxin A 4 is an endogenous allosteric enhancer of CB 1 cannabinoid receptor

Cited by 161 publications

References 52 publications

Biased Agonism and Biased Allosteric Modulation at the CB1Cannabinoid Receptor

Biased Agonism and Biased Allosteric Modulation at the CB1Cannabinoid Receptor

Molecular Targets of Cannabidiol in Neurological Disorders

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Contact Info

Product

Resources

About

Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor