Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB
1
and CB
2
receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC
50
(a measure of potency) and E
max
(a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB
2
receptor than at the CB
1
receptor and (
S
)-enantiomers had an enhanced potency to both receptors over the (
R
)-enantiomers. The relative potency of the enantiomers to the CB
2
receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (
R
)-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials (
n
= 16), found 5F-MDMB-PINACA (<1.0–91.5 mg/g herbal material) and AMB-FUBINACA (15.5–58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the (
S
)-enantiomer predominated in all samples (93.6–99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the “intrinsic” potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.
SummaryThe hetero-Diels–Alder reaction between a nitroso dienophile and a conjugated diene to give the 3,6-dihydro-2H-1,2-oxazine scaffold is useful for the synthesis of many biologically interesting molecules due to the diverse opportunities created by subsequent transformations of the resulting 1,2-oxazine ring. This review discusses the rationale for the observed regio- and stereoselectivity and the methods developed in recent years used to control and improve the stereo- and regioselectivity for the synthesis of 1,2-oxazine scaffolds.
Perfluorocyclopentadiene partakes in the Diels-Alder reaction (a) as a diene in its thermal reactions with dimethyl acetylenedicarboxylate ( -dimethyl 1,2,3.4,7,7-hexafluorobicylo [2,2,1] hepta-2,5-diene-5,6-dicarboxylate).ethylene (4 1,2,3,4,7,7-hexafluorobicyclo[2.2.1] hept-2-ene), acetylene (4 1,2,3.4,7,7-hexafIuorobicyclo-
3,6-Dihydro-2H-1,2-oxazines were synthesised via solid-phase synthesis to afford mixtures of stereo- and regioisomers. The analytical conditions for the analysis of the isomer ratio suitable for checking of reaction conditions of possible stereoselective synthesis were developed with the use of HPLC including chiral stationary phases (CSPs) based on chiral polysaccharide derivatives immobilized on a silica support. It was found that those CSPs based on an amylose backbone were more efficient than those based on cellulose for the molecules investigated. Additionally, analytical samples without complete purification could be separated under the same conditions. The asymmetric induction causing the difference in the stereoisomer ratio was observed, when an oxazine ring was built up directly on a chiral moiety. A chiral aminoacid separated from the construction site by an achiral aromatic ring did not influence the ratio of stereoisomers. The analytical conditions developed were thus verified for use in the optimisation of the regio- and stereoselective synthesis of 3,6-dihydro-2H-1,2-oxazines. The conditions are suitable for solid-phase synthesis methodology often used in high throughput synthesis of biologically active compounds
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