Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain

Adam, Jennifer; Clark, John K.; Davies, Keneth; Everett, Kathryn; Fields, Ruth; Francis, Stuart; Jeremiah, Fiona; Kiyoi, Takao; Maidment, Maurice S.; Morrison, Angus J.; Ratcliffe, Paul; Prosser, Alan; Schulz, Jürgen; Wishart, Grant; Baker, James Α.; Boyce, Susan; Campbell, Robert A.; Cottney, Jean; Deehan, Maureen R.; Martin, Iain

doi:10.1016/j.bmcl.2012.02.048

Cited by 16 publications

(19 citation statements)

References 35 publications

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“…There is evidence too that a synthetic analogue of D 8 -THC, ajulemic acid (CT-3), may ameliorate neuropathic pain mainly by targeting cannabinoid receptors located outside the blood-brain barrier [3]. Five further examples of peripherally restricted cannabinoids that can induce antinociception in animal models are the cannabilactone, AM1710 [11]; the 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative, compound 44 [12]; the 5-sulphonylbenzimidazole derivative, compound 49 [13]; the g-carboline, compound 29 [14]; and the thiadiazole, compound LBP1 [15]. AM1710 reduces signs of pain elicited by thermal (but not mechanical) stimulation of the rat hind paw at doses that do not produce signs of unwanted CNS side-effects [11].…”

Section: Direct Activation Of Cannabinoid Receptors Located Outside Tmentioning

confidence: 99%

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

Pertwee

2012

Phil. Trans. R. Soc. B

312

269

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Human tissues express cannabinoid CB 1 and CB 2 receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB 1 /CB 2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; D 9 -tetrahydrocannabinol (D 9 -THC)) and Sativex (D 9 -THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB 2 receptors, and/or (v) adjunctive 'multi-targeting'.

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Section: Direct Activation Of Cannabinoid Receptors Located Outside Tmentioning

confidence: 99%

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

Pertwee

2012

Phil. Trans. R. Soc. B

312

269

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“…The plasma area under the curve for AM841 was 3.75 ± 0.50 min·μg·mL −1 and the brain 0.20 ± 0.02 min·μg·mL −1 , giving a ratio of 0.05. By comparison, brain-penetrant CBs have ratios of 1 or more (Dyson et al, 2005;Rahn et al, 2011;Adam et al, 2012).…”

Section: Am841 Behaves As a Peripherally Restricted Cb 1 Receptor Agomentioning

confidence: 99%

AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner

Keenan

Storr

Thakur

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSECannabinoid (CB) ligands have been demonstrated to have utility as novel therapeutic agents for the treatment of pain, metabolic conditions and gastrointestinal (GI) disorders. However, many of these ligands are centrally active, which limits their usefulness. Here, we examine a unique novel covalent CB receptor ligand, AM841, to assess its potential for use in physiological and pathophysiological in vivo studies. EXPERIMENTAL APPROACHThe covalent nature of AM841 was determined in vitro using electrophysiological and receptor internalization studies on isolated cultured hippocampal neurons. Mouse models were used for behavioural analysis of analgesia, hypothermia and hypolocomotion. The motility of the small and large intestine was assessed in vivo under normal conditions and after acute stress. The brain penetration of AM841 was also determined. KEY RESULTSAM841 behaved as an irreversible CB1 receptor agonist in vitro. AM841 potently reduced GI motility through an action on CB1 receptors in the small and large intestine under physiological conditions. AM841 was even more potent under conditions of acute stress and was shown to normalize accelerated GI motility under these conditions. This compound behaved as a peripherally restricted ligand, showing very little brain penetration and no characteristic centrally mediated CB1 receptor-mediated effects (analgesia, hypothermia or hypolocomotion). CONCLUSIONS AND IMPLICATIONSAM841, a novel peripherally restricted covalent CB1 receptor ligand that was shown to be remarkably potent, represents a new class of potential therapeutic agents for the treatment of functional GI disorders.

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“…Therefore, Adam et al structurally modified a series of brain penetrant CB1 receptor agonists, using a strategy of increasing polar surface area to reduce brain penetration, while maintaining in vitro potency and oral drug-like physicochemical properties. Among synthesized compounds, compound 30 exhibited the most antiallodynic and antihyperalgesic activity in a rat model of neuropathic pain [59].…”

Section: Cb1 Cannabinoid Receptor Agonists/antagonistsmentioning

confidence: 99%

Substituted oxadiazoles: a patent review (2010 – 2012)

Zarghi

Hajimahdi

2013

Expert Opinion on Therapeutic Patents

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Oxadiazoles have been used frequently in drug-like molecules as bioisosteres for ester and amide functionalities and displayed numerous prominent pharmacological effects. The broad pharmacological profile of oxadiazole derivatives has attracted the attention of many researchers to explore this scaffold to its multiple potential against several activities. Therefore, oxadiazole motif is likely to be present in other therapeutic molecules in the future.

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Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain

Cited by 16 publications

References 35 publications

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner

Substituted oxadiazoles: a patent review (2010 – 2012)

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