In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018
| Autor: | Richard C. Kevin, Michelle Glass, Daniel Gadsden Barrus, Jenny L. Wiley, Purvi R. Patel, Thomas F. Gamage, Timothy W. Lefever, Iain S. McGregor, David B. Finlay, Megan Grabenauer, Brian F. Thomas |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cannabinoid receptor Synthetic Drugs medicine.medical_treatment Clinical Biochemistry Carbazoles Naphthalenes Pharmacology Toxicology Biochemistry Partial agonist Article Body Temperature Receptor Cannabinoid CB2 Mice 03 medical and health sciences Behavioral Neuroscience 0302 clinical medicine Receptor Cannabinoid CB1 Rimonabant Microsomes mental disorders Cyclic AMP medicine Cannabinoid receptor type 2 Animals Humans Potency Rats Long-Evans Dronabinol Receptor Biological Psychiatry Cannabinoid Receptor Agonists Mice Inbred ICR Behavior Animal Chemistry Rats 030227 psychiatry Mice Inbred C57BL HEK293 Cells Liver lipids (amino acids peptides and proteins) Cannabinoid Locomotion 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Pharmacol Biochem Behav |
| ISSN: | 0091-3057 |
| Popis: | Synthetic cannabinoid receptor agonists (SCRAs) possess high abuse liability and complex toxicological profiles, making them serious threats to public health. EG-018 is a SCRA that has been detected in both illicit products and human samples, but it has received little attention to date. The current studies investigated EG-018 at human CB(1) and CB(2) receptors expressed in HEK293 cells in [(3)H]CP55,940 competition binding, [(35)S]GTPγS binding and forskolin-stimulated cAMP production. EG-018 was also tested in vivo for its ability to produce cannabimimetic and abuse-related effects in the cannabinoid tetrad and THC drug discrimination, respectively. EG-018 exhibited high affinity at CB(1) (21 nM) and at CB(2) (7 nM), but in contrast to typical SCRAs, behaved as a weak partial agonist in [(35)S]GTPγS binding, exhibiting lower efficacy but greater potency, than that of THC at CB(1) and similar potency and efficacy at CB(2). EG-018 inhibited forskolin-stimulated cAMP with similar efficacy but lower potency, compared to THC, which was likely due to high receptor density facilitating saturation of this signaling pathway. In mice, EG-018 (100 mg/kg, 30 min) administered intraperitoneally (i.p.) did not produce effects in the tetrad or drug discrimination nor did it shift THC’s ED(50) value in drug discrimination when administered before THC, suggesting EG-018 has negligible occupancy of brain CB(1) receptors following i.p. administration. Following intravenous (i.v.) administration, EG-018 (56 mg/kg) produced hypomotility, catalepsy, and hypothermia, but only catalepsy was blocked by the selective CB(1) antagonist rimonabant (3 mg/kg i.v.). Additional studies of EG-018 and its structural analogues could provide further insight into how cannabinoids exert efficacy through the cannabinoid receptors. |
| Databáze: | OpenAIRE |
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