γ-Carbolines: A novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration

Cheng, Yun‐Xing; Pourashraf, Mehrnaz; Luo, Xi; Srivastava, Sanjay K.; Walpole, Christopher; Salois, Dominic; St-Onge, Stéphane; Payza, Kemal; Lessard, Étienne; Yu, Xiao Hong; Tomaszewski, Mirosław J.

doi:10.1016/j.bmcl.2011.12.124

Cited by 14 publications

(13 citation statements)

References 24 publications

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“…In addition, Cheng et al . suggested a group of γ‐carbolines as a class of SCRAs combining water solubility and low CNS penetration, which could explain both medical potential and (previously postulated) low (central) toxicity 28 . However, contrasting with these reports are a number of fatalities reported in Australia, in which even sub‐nanogram per millilitre concentrations of Cumyl‐PEGACLONE in blood were considered as highly probable to have contributed to death 13 .…”

Section: Discussionmentioning

confidence: 97%

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

Janssens

Cannaert

Connolly

et al. 2020

Drug Testing and Analysis

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Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances monitored in Europe. SCRAs are known to typically exert higher cannabinoid activity than tetrahydrocannabinol from cannabis, thereby entailing a greater health risk. Both Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were not controlled by the national legislation upon their first detection in Germany in 2016 and 2017, respectively, and have been linked to several fatalities. In this study, the CB1 receptor activity of these compounds, together with two newly synthesized structural isomers (Cumyl‐PEGACLONE ethylbenzyl isomer and n‐propylphenyl isomer), was assessed using two different in vitro receptor‐proximal bioassays, monitoring the recruitment of either β‐arrestin2 (β‐arr2) or a modified G protein (mini‐Gαi) to the activated CB1 receptor. In terms of both potency and relative efficacy, Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were found to exert strong CB1 activation, with sub‐nanomolar EC50 values and efficacy values exceeding those of the reference agonist JWH‐018 threefold (β‐arr2 assay) or almost twofold (mini‐Gαi assay). The ethylbenzyl and n‐propylphenyl isomers exhibited a strongly reduced CB1 activity (EC50 values >100 nM; efficacy <40% relative to JWH‐018), which is hypothesized to originate from steric hindrance in the ligand‐binding pocket. None of the evaluated compounds exhibited significant biased agonism. In conclusion, the functional assays applied here allowed us to demonstrate that 5‐fluorination of Cumyl‐PEGACLONE is not linked to an intrinsically higher CB1 activation potential and that the ethylbenzyl and n‐propylphenyl isomers yield a strongly reduced CB1 activation.

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Section: Discussionmentioning

confidence: 97%

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

Janssens

Cannaert

Connolly

et al. 2020

Drug Testing and Analysis

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“…5) as the first of a new γ-carboline class of cannabinoids. 109 19 demonstrated moderate affinity for both CB receptors (hCB 1 K i = 143 nM, hCB 2 K i = 14 nM) and functioned suitably as an agonist (rCB 1 EC 50 = 1440 nM, E max = 47%). Additionally, 18 had reasonable aqueous solubility (>3 mg mL −1 at pH 7.4), unlike many classes of cannabinoids.…”

Section: Peripherally-restricted Cb 1 Agonistsmentioning

confidence: 99%

Selective modulation of the cannabinoid type 1 (CB₁) receptor as an emerging platform for the treatment of neuropathic pain

Banister

Kumar

et al. 2019

Med. Chem. Commun.

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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

311

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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γ-Carbolines: A novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration

Cited by 14 publications

References 24 publications

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

Selective modulation of the cannabinoid type 1 (CB₁) receptor as an emerging platform for the treatment of neuropathic pain

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

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γ-Carbolines: A novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration

Cited by 14 publications

References 24 publications

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB1 receptor: Fluorination versus isomer exploration

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB1 receptor: Fluorination versus isomer exploration

Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain

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

Contact Info

Product

Resources

About

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

Selective modulation of the cannabinoid type 1 (CB₁) receptor as an emerging platform for the treatment of neuropathic pain