Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases

Chicca, Andrea; Arena, Chiara; Manera, Clementina

doi:10.2174/1574889810999160603185126

Cited by 28 publications

(31 citation statements)

References 122 publications

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“…pharmacological potential of this complex signaling network (11,12,27,28). However, the lack of selective inhibitors of EC membrane transport has prevented an unambiguous biochemical and pharmacological characterization of this process.…”

Section: Discussionmentioning

confidence: 99%

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Chicca

Nicolussi

Bartholomäus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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155

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The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived -substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC = 10 nM) inhibitor -(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

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Section: Discussionmentioning

confidence: 99%

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Chicca

Nicolussi

Bartholomäus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

155

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“…Nowadays, several pharmacological tools are available to target endocannabinoid neurotransmission . Several established cannabinoid receptor direct agonists, which directly activate cannabinoid receptors, have been synthesized.…”

Section: Docking Simulations Of Cannabinoids Binding To Fa‐free and Fmentioning

confidence: 99%

Human serum albumin: A modulator of cannabinoid drugs

et al. 2017

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The endocannabinoid system is a unique neuromodulatory system that affects a wide range of biological processes and maintains the homeostasis in all mammal body systems. In recent years, several pharmacological tools to target endocannabinoid neurotransmission have been developed, including direct and indirect cannabinoid agonists and cannabinoid antagonists. Due to their hydrophobic nature, cannabinoid agonists and antagonists need to bind specific transporters to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key determinant of drug pharmacokinetics. As HSA binds both the endocannabinoid anandamide and the active ingredient of Cannabis sativa, Δ-9-tetrahydrocannabinol, we hypothesize that HSA can be the most important carrier of cannabinoid drugs. In silico docking observations strongly indicate that HSA avidly binds the indirect cannabinoid agonists URB597, AM5206, JZL184, JZL195, and AM404, the direct cannabinoid agonists WIN55,212-2 and CP55,940, and the prototypical cannabinoid antagonist/inverse agonist SR141716. Values of the free energy for cannabinoid drugs binding to HSA range between -5.4 kcal mol and -10.9 kcal mol . Accounting for the HSA concentration in vivo (∼ 7.5 × 10 M), values of the free energy here determined suggest that the formation of the HSA:cannabinoid drug complexes may occur in vivo. Therefore, HSA appears to be an important determinant for cannabinoid efficacy and may guide the choice of the drug dose regimen to optimize drug efficacy and to avoid drug-related toxicity. © 2017 IUBMB Life, 69(11):834-840, 2017.

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“…Thereafter, the endocannabinoid molecule is either removed by a putative reuptake transporter back into the postsynaptic terminal or it is enzymatically degraded and thus inactivated. AEA is degraded by fatty acid amide hydrolase (FAAH) enzymes and 2-AG by monoacylglycerol lipase (MAGL) [45,46].…”

Section: Cannabinoid Receptors and Endocannabinoidsmentioning

confidence: 99%

“…At the same time, the search for more specifically-acting, therapeutically useful SCs continues. Among the new developments are synthetic agonists and antagonists that selectively bind to the various cannabinoid receptor types; at the same time, agents that interact with endocannabinoid synthesis, reuptake, and degradation are also being developed [45]. There is evidence that such new drugs may become useful in the treatment of pain and neuro-psychiatric disorders.…”

Section: Cannabinoid Effects In Humansmentioning

confidence: 99%

The ongoing challenge of novel psychoactive drugs of abuse. Part I. Synthetic cannabinoids (IUPAC Technical Report)

Abbate

Schwenk

Presley

et al. 2018

Pure and Applied Chemistry

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In the past decade, the world has experienced a large increase in the number of novel compounds appearing on the illicit drug market for recreational purposes. Such substances are designed to circumvent governmental regulations; the illegal drug manufacturers take a known psychoactive compound reported in the scientific literature and slightly modify its chemical structure in order to produce analogues that will mimic the pharmacological activity of the original substance. Many of these novel substances are sold via the Internet. Among the various chemical classes, synthetic cannabinoid receptor modulators, commonly referred to as “synthetic cannabinoids” have been at the forefront, as demonstrated by the frequency of drug seizures, numerous severe toxic effects, and fatalities associated with some of these substances. This review presents the chemical structures of relevant synthetic cannabinoids and describes their mechanism of action, pharmacological features, metabolic pathways, and structure-activity relationships. It illustrates the approaches used in forensic testing, both for bulk analysis (drug seizures) and for analytical toxicology (biological matrices) and discusses aspects of regulation surrounding this drug class. This report is intended to provide pertinent information for the purposes of informing scientific, medical, social, and governmental bodies about this ever-evolving recreational drug class and the challenges it poses worldwide.

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Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases

Cited by 28 publications

References 122 publications

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Human serum albumin: A modulator of cannabinoid drugs

The ongoing challenge of novel psychoactive drugs of abuse. Part I. Synthetic cannabinoids (IUPAC Technical Report)

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