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Synthesis and in Vitro Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA
- Source :
- ACS Chemical Neuroscience. 11:4434-4446
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
Abstract
- Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances (NPS) with structurally diverse compounds emerging each year. Due to the rapid pace at which these drugs enter the market, there is often little or nil information regarding the pharmacology of these substances despite widespread human use. In this study, 12 recently emerged SCRAs (reported between 2018 and 2020) were synthesized, analytically characterized, and pharmacologically evaluated using a live cell-based nanoluciferase complementation reporter assay that monitors in vitro cannabinoid receptor type 1 (CB1) activation via its interaction with beta-arrestin 2 (beta arr2). All synthesized SCRAs acted as agonists of CB1, although differences in potency (EC50 = 2.33-5475 nM) and efficacy (E-max = 37-378%) were noted, and several structure-activity relationships were identified. SCRAs featuring indazole cores (EC50 = 2.33-159 nM) were generally of equal or greater potency than indole analogues (EC so = 32.9-330 nM) or 7-azaindole derivatives (EC50 = 64.0-5475 nM). Interestingly, with the exception of APP-BINACA (E max = 75.7%) and SF-A-P7AICA (E-max = 37.4%), all SCRAs showed greater efficacy than the historical SCRA JWH-018 to which responses were normalized (E-max = 142-378%). The most potent CBI agonists in the study were ADB-BINACA (EC50 = 6.36 nM), 4F-MDMB-BINACA (EC50 = 7.39 nM), and MDMB-4en-PINACA (EC50 = 2.33 nM). Notably, all of these SCRAs featured an indazole core as well as a "bulky" tert-butyl moiety in the pendant amino acid side chain. This study confirms that recently detected SCRAs 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-ABP7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA were all able to activate the CB1 receptor in vitro, albeit to different extents, and are potentially psychoactive in vivo. These results indicate that further evaluation of these widely used NPS is warranted to better understand the risks associated with human consumption of these drugs.
- Subjects :
- Indole test
0303 health sciences
Indazole
Cannabinoid receptor
Physiology
Cognitive Neuroscience
Cannabinoid Receptor Agonists
Cell Biology
General Medicine
Pharmacology
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
chemistry
In vivo
Cannabinoid receptor type 1
Synthetic cannabinoids
medicine
Potency
030217 neurology & neurosurgery
030304 developmental biology
medicine.drug
Subjects
Details
- ISSN :
- 19487193
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Neuroscience
- Accession number :
- edsair.doi...........e961e1f27c1557f3ad46e9e7afd42975