Reversing binding sensitivity to A147T translocator protein

The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [11C]DPA-713, has been hampered by the presence of a common polymorphism (A147T TSPO), at which all second-generation TSPO ligands lose affinity. Little is known about what drives binding at A147T compared to WT TSPO. This study aimed to identify moieties in DPA-713, and related derivatives, that influence binding at A147T compared to WT TSPO. We found changes to the nitrogen position and number in the heterocyclic core influences affinity to WT and A147T to a similar degree. Hydrogen bonding groups in molecules with an indole core improve binding at A147T compared to WT, a strategy that generated compounds that possess up to ten-times greater affinity for A147T. These results should inform the future design of compounds that bind both A147T and WT TSPO for use in neuroinflammation imaging

Acute myocardial infarction, associated with the use of a synthetic adamantyl-cannabinoid: a case report

BACKGROUND: “Legal highs” are novel psychoactive substances that have evaded statutory control. Synthetic cannabinoid compounds with adamantane moieties have recently been identified, which have high potency at target receptors and are undetectable on conventional toxicology testing. However, little is known about any harmful effects, and their potential to cause serious ill health. We describe a case of myocardial infarction following the use of this class of drug. CASE PRESENTATION: We report the case of a 39-year-old man admitted after an out-of-hospital cardiac arrest, in whom ECG and elevated cardiac enzymes confirmed ST-elevation myocardial infarction. Normal coronary perfusion was restored after thrombectomy and coronary artery stenting. In the hours preceding his admission, the patient is known to have consumed the legal high product “Black Mamba”. Subsequent urine testing confirmed the presence of an adamantyl-group synthetic cannabinoid, whilst cannabis, cocaine, amphetamines and other drugs of abuse were not detected. CONCLUSION: The use of legal highs is being increasingly recognised, but the chemical compositions and physiological effects of these drugs are poorly characterised and are continually changing. Synthetic cannabinoids, rarely identified on toxicological testing, can be linked to serious adverse cardiovascular events. This case highlights the importance of testing for novel psychoactive compounds, and recognising their potential to cause life-threatening conditions

In vitro evaluation of the interaction of the cannabis constituents cannabichromene and cannabichromenic acid with ABCG2 and ABCB1 transporters.

Cannabichromene (CBC) and cannabichromenic acid (CBCA) are cannabis constituents currently under evaluation for their therapeutic potential, but their pharmacological properties have not been thoroughly investigated. The most studied ATP-binding cassette (ABC) transporters, ABC subfamily G member 2 (ABCG2) and ABC subfamily B member 1 (ABCB1) limit absorption of substrate drugs in the gut and brain. Moreover, inhibitors of these proteins can lead to clinically significant drug-drug interactions (DDIs). The current study sought to examine whether CBC and CBCA affect ABCB1 and ABCG2 to advance their basic pharmacological characterisation. The plant cannabinoids CBC and CBCA were screened in vitro in a bidirectional transport assay to determine whether they were substrates and/or inhibitors of ABCB1 and ABCG2. Transwell assays with polarized epithelial Madin-Darby Canine Kidney II (MDCK) cells expressing ABCB1 or ABCG2 were used. Samples were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS). CBCA was found to be an ABCB1 substrate, but not an ABCG2 substrate. CBC was not a substrate of either transporter. Neither CBCA nor CBC inhibited ABCB1 transport of prazosin or ABCG2 transport of digoxin. In silico molecular docking suggested CBCA binds ABCB1 in the access tunnel and the central binding pocket. CBC, an agent with anticonvulsant, anti-inflammatory and anti-depressant properties, is not a substrate or inhibitor of ABCB1 or ABCG2, which is favourable to its therapeutic development. CBCA is an ABCB1 substrate in vitro which might contribute to its poor absorption. These findings provide important basic pharmacological data to assist the therapeutic development of these cannabis constituents

Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO).

Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay