ORCID Profile
0000-0003-3941-4537
Current Organisation
The University of Auckland
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Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2019
DOI: 10.1101/589341
Abstract: Synthetic cannabinoids are a commonly used class of recreational drugs that can have significant adverse effects. There have been sporadic reports of co-consumption of illicit drugs with rodenticides such as warfarin and brodifacoum (BFC) over the past 20 years but recently, hundreds of people have been reported to have been poisoned with a mixture of synthetic cannabinoids and BFC. We have sought to establish whether BFC directly affects cannabinoid receptors, or their activation by the synthetic cannabinoid CP55940 or the phytocannabinoid Δ 9 -tetrahydrocannabinol (Δ 9 -THC). The effects of BFC on the hyperpolarization of wild type AtT20 cells, or AtT20 cells stably expressing human CB 1 - and CB 2 -mediated receptors, were studied using a fluorescent assay of membrane potential. The effects of BFC on CB 1 and CB 2 mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) activation was measured using a BRET assay of cAMP levels in HEK 293 cells stably expressing human CB 1 and CB 2 . BFC did not activate CB 1 or CB 2 receptors, or affect the hyperpolarization of wild type AtT20 cells produced by somatostatin. BFC (10 µ M) did not affect the hyperpolarization of AtT20-CB 1 or AtT20-CB 2 cells produced by CP55940 or Δ 9 -THC. BFC (1 µ M) did not affect the inhibition of forskolin-stimulated AC activity by CP55940 in HEK 293 cells expressing CB 1 or CB 2 . BFC (1 µ M) also failed to affect the desensitization of CB 1 and CB 2 signalling produced by prolonged (30 min) application of CP55940 or Δ 9 -THC to AtT20 cells. BFC is not a cannabinoid receptor agonist, and appeared not to affect cannabinoid receptor activation. Our data suggests there is no pharmacodynamic rationale for mixing BFC with synthetic cannabinoids, however, it does not speak to whether BFC may affect synthetic cannabinoid metabolism or biodistribution. The reasons underlying the mixing of BFC with synthetic cannabinoids are unknown, and it remains to be established whether the “contamination” was deliberate or accidental. However, the consequences for people who ingested the mixture were often serious, and sometimes fatal, but this seems unlikely to be due to BFC action at cannabinoid receptors.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-03-2020
DOI: 10.1126/SCISIGNAL.AAZ3140
Abstract: Low intrinsic efficacy can explain the reduced side effects of apparently biased μ-opioid receptor agonists.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.DRUDIS.2019.10.004
Abstract: Monoacylglycerol lipase (MAGL) is a major endocannabinoid hydrolyzing enzyme and can be regulated to control endogenous lipid levels in the brain. This review highlights the pharmacological roles and in vivo PET imaging of MAGL in brain.
Publisher: Wiley
Date: 10-2013
DOI: 10.1111/BPH.12329
Publisher: PeerJ
Date: 12-04-2021
DOI: 10.7717/PEERJ.11175
Abstract: Pregabalin and gabapentin improve neuropathic pain symptoms but there are emerging concerns regarding their misuse. This is more pronounced among patients with substance use disorder, particularly involving opioids. Co-ingestion of gabapentinoids with opioids is increasingly identified in opioid related deaths, however, the molecular mechanism behind this is still unclear. We have sought to determine whether pregabalin or gabapentin directly modulates acute μ receptor signaling, or μ receptor activation by morphine. The effects of pregabalin and gabapentin were assessed in HEK 293 cells stably transfected with the human μ receptor. Their effect on morphine induced hyperpolarization, cAMP production and ERK phosphorylation were studied using fluorescent-based membrane potential assay, bioluminescence based CAMYEL assay and ELISA assay, respectively. Pregabalin/gabapentin effects on morphine-induced hyperpolarization were also investigated in AtT20 cells. Pregabalin or gabapentin (1 µM, 100 µM each) did not activate the µ receptor or affect K channel activation or ERK phosphorylation produced by morphine. Neither drug affected the desensitization of K channel activation produced by prolonged (30 min) application of morphine. Gabapentin (1 µM, 100 µM) and pregabalin (1 µM) did not affect inhibition of forskolin-stimulated cAMP production by morphine. However, pregabalin (100 µM) potentiated forskolin mediated cAMP production, although morphine still inhibited cAMP levels with a similar potency to control. Pregabalin or gabapentin did not activate or modulate µ receptor signaling in three different assays. Our data do not support the hypothesis that gabapentin or pregabalin augment opioid effects through direct or allosteric modulation of the µ receptor. Pregabalin at a high concentration increases cAMP production independent of morphine. The mechanism of enhanced opioid-related harms from co-ingestion of pregabalin or gabapentin with opioids needs further investigation.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8MD00448J
Abstract: High affinity, cannabinoid type 2 receptor selective ligand.
Publisher: American Chemical Society (ACS)
Date: 14-12-2022
Publisher: Wiley
Date: 13-01-2023
Abstract: G protein‐coupled receptor (GPCR) ligand prodrugs that can be released on demand with spatiotemporal control are powerful chemical tools that can assist in elucidating the consequences of GPCR activation or blockade at precise locations and times both in vitro and in vivo . Cannabinoid receptor prodrugs are of interest from both a drug delivery perspective and as tools to unravel the potential for differential signaling responses to be produced from cannabinoid receptor populations in distinct subcellular locations. Herein, the development and characterization of a cannabinoid type 2 receptor agonist prodrug is described, based on a 4‐diethylamino‐coumarylidenemalononitrilemethyl (DEACM‐MN) photo caging moiety linked via a carbonate to a chromenopyrazole cannabinoid ligand. This prodrug showed rapid photolysis with 450–455 nm light and good stability in biologically relevant buffer. The formation of various coumarin products alongside drug release was studied in different conditions. Radioligand binding assays were conducted with the prodrug, which revealed a significantly decreased human cannabinoid type 2 receptor binding affinity than the active chromenopyrazole parent ligand.
Publisher: Wiley
Date: 17-11-2015
DOI: 10.1111/BPH.13341
No related grants have been discovered for Natasha Grimsey.