Differential activation of G protein‐mediated signaling by synthetic cannabinoid receptor agonists

Sachdev, Shivani; Banister, Samuel D.; Santiago, Marina; Bladen, Chris; Kassiou, Michael; Connor, Mark

doi:10.1002/prp2.566

Cited by 18 publications

(10 citation statements)

References 52 publications

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“…Even though a chemical prototype may have a long history of use and considerable literature, each new chemical entity is essentially a pharmacological unknown with the inherent potential to produce unanticipated effects in users or their descendants [ 117 ]. For example, G-protein promiscuity and signaling bias has been shown to be an important pharmacological property that may differentiate between phytocannabinoids and synthetic cannabimimetics and their relative ability to produce tolerance and dependence and other pharmacological effects [ 136 , 137 ]. Synthetic alkyl indole compounds are able to activate CB 1 and CB 2 cannabinoid receptors, and the selectivity can make a difference in outcomes of G protein signaling (see Figure 10 ).…”

Section: The Ultimate Diversion Of Cannabimimetic Indoles: Spice/k2mentioning

confidence: 99%

The Spicy Story of Cannabimimetic Indoles

Howlett

Thomas²,

Huffman

2021

Molecules

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The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.

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Section: The Ultimate Diversion Of Cannabimimetic Indoles: Spice/k2mentioning

confidence: 99%

The Spicy Story of Cannabimimetic Indoles

Howlett

Thomas²,

Huffman

2021

Molecules

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“…The most compelling possibility is that the difference in the long-term effects may result from subtle distinctions in the pharmacodynamics of HU-210, be they in its binding to non-ECS receptors (Pertwee, 2010;Wiley et al, 2016), or in the signaling pathways triggered by CB1R binding (Diez-Alarcia et al, 2016;Sachdev et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior

Farinha-Ferreira¹,

Rei²,

Fonseca-Gomes³

et al. 2021

Preprint

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Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely ∆9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.

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“…The increased Ca 2+ can then be quantified using a Ca 2+ -sensitive fluorescent dye (e.g., Furo-2, Fluo-4, etc.). Alternatively, cAMP levels are measured in real-time in CB1 receptor cells using a bioluminescence resonance energy transfer (BRET) assay ( Figure 3 C) [ 48 , 50 , 52 ]. BRET involves the transfer of energy from a donor luminescence enzyme to an acceptor fluorophore.…”

Section: Cb1 Receptor Signal Transduction Assaysmentioning

confidence: 99%

“…While the CB1 receptor predominately couples to G i , signaling through G s and G q has also been reported [ 31 , 32 ]. In the presence of pertussis toxin to inhibit G i /G o , high concentrations of SCs such as WIN 55,212-2, CP-55,940, JWH-018 and AB-FUBINACA increase cAMP levels above those produced by forskolin [ 48 , 50 ]. Interestingly, increases in cAMP are not observed with THC under these conditions, again implying that ligand-receptor interactions modulate G protein coupling [ 48 , 50 ].…”

Section: Summary Of Sc Molecular Pharmacologymentioning

confidence: 99%

“…In the presence of pertussis toxin to inhibit G i /G o , high concentrations of SCs such as WIN 55,212-2, CP-55,940, JWH-018 and AB-FUBINACA increase cAMP levels above those produced by forskolin [ 48 , 50 ]. Interestingly, increases in cAMP are not observed with THC under these conditions, again implying that ligand-receptor interactions modulate G protein coupling [ 48 , 50 ]. In addition to stimulating G i and G s , WIN 55,212-2 acts via the CB1 receptor/G q /phospholipase C pathway to increase intracellular Ca 2+ levels in HEK293 cells and cultured hippocampal neurons [ 32 ].…”

Section: Summary Of Sc Molecular Pharmacologymentioning

confidence: 99%

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Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling

Walsh

Andersen

2020

IJMS

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Synthetic cannabinoids (SCs) are a class of new psychoactive substances (NPSs) that exhibit high affinity binding to the cannabinoid CB1 and CB2 receptors and display a pharmacological profile similar to the phytocannabinoid (-)-trans-Δ9-tetrahydrocannabinol (THC). SCs are marketed under brand names such as K2 and Spice and are popular drugs of abuse among male teenagers and young adults. Since their introduction in the early 2000s, SCs have grown in number and evolved in structural diversity to evade forensic detection and drug scheduling. In addition to their desirable euphoric and antinociceptive effects, SCs can cause severe toxicity including seizures, respiratory depression, cardiac arrhythmias, stroke and psychosis. Binding of SCs to the CB1 receptor, expressed in the central and peripheral nervous systems, stimulates pertussis toxin-sensitive G proteins (Gi/Go) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca2+ channels and the activation of G protein-gated inward rectifier (GIRK) channels. This combination of signaling effects dampens neuronal activity in both CNS excitatory and inhibitory pathways by decreasing action potential formation and neurotransmitter release. Despite this knowledge, the relationship between the chemical structure of the SCs and their CB1 receptor-mediated molecular actions is not well understood. In addition, the potency and efficacy of newer SC structural groups has not been determined. To address these limitations, various cell-based assay technologies are being utilized to develop structure versus activity relationships (SAR) for the SCs and to explore the effects of these compounds on noncannabinoid receptor targets. This review focuses on describing and evaluating these assays and summarizes our current knowledge of SC molecular pharmacology.

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Differential activation of G protein‐mediated signaling by synthetic cannabinoid receptor agonists

Cited by 18 publications

References 52 publications

The Spicy Story of Cannabimimetic Indoles

The Spicy Story of Cannabimimetic Indoles

Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior

Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling

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