Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling
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 (-)-<i>trans</i>-Δ<sup>9</sup>-tetrahydrocannabinol...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/17/6115 |
| _version_ | 1797555669432270848 |
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| author | Kenneth B. Walsh Haley K. Andersen |
| author_facet | Kenneth B. Walsh Haley K. Andersen |
| author_sort | Kenneth B. Walsh |
| collection | DOAJ |
| description | 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 (-)-<i>trans</i>-Δ<sup>9</sup>-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 (G<sub>i</sub>/G<sub>o</sub>) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca<sup>2+</sup> 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. |
| first_indexed | 2024-03-10T16:51:50Z |
| format | Article |
| id | doaj.art-7200d5d149154d9cbe82b0c0e9235dc0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:51:50Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7200d5d149154d9cbe82b0c0e9235dc02023-11-20T11:17:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012117611510.3390/ijms21176115Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell SignalingKenneth B. Walsh0Haley K. Andersen1Department of Pharmacology, Physiology & Neuroscience, University of South Carolina, School of Medicine, Columbia, SC 29208, USADepartment of Pharmacology, Physiology & Neuroscience, University of South Carolina, School of Medicine, Columbia, SC 29208, USASynthetic 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 (-)-<i>trans</i>-Δ<sup>9</sup>-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 (G<sub>i</sub>/G<sub>o</sub>) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca<sup>2+</sup> 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.https://www.mdpi.com/1422-0067/21/17/6115CB1 receptorssynthetic cannabinoidsmolecular pharmacologycell signaling assays |
| spellingShingle | Kenneth B. Walsh Haley K. Andersen Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling International Journal of Molecular Sciences CB1 receptors synthetic cannabinoids molecular pharmacology cell signaling assays |
| title | Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling |
| title_full | Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling |
| title_fullStr | Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling |
| title_full_unstemmed | Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling |
| title_short | Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling |
| title_sort | molecular pharmacology of synthetic cannabinoids delineating cb1 receptor mediated cell signaling |
| topic | CB1 receptors synthetic cannabinoids molecular pharmacology cell signaling assays |
| url | https://www.mdpi.com/1422-0067/21/17/6115 |
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