Abstract
Recently, carboxamide-type synthetic cannabinoids have been distributed globally as new psychoactive substances (NPS). Some of these compounds possess asymmetric carbon, which is derived from an amide moiety composed of amino acid derivatives (i.e., amides or esters of amino acids). In this study, we synthesized both enantiomers of synthetic cannabinoids, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(2-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA 2-fluorobenzyl isomer), N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (APP-CHMINACA), ethyl [1-(5-fluoropentyl)-1H-indazole-3-carbonyl]valinate (5F-EMB-PINACA), ethyl [1-(4-fluorobenzyl)-1H-indazole-3-carbonyl]valinate (EMB-FUBINACA), and methyl 2-[1-(4-fluorobenzyl)-1H-indole-3-carboxamido]-3,3-dimethylbutanoate (MDMB-FUBICA), which were reported as NPS found in Europe from 2014 to 2015, to evaluate their activities as CB1/CB2 receptor agonists. With the exception of (R) MDMB-FUBICA, all of the tested enantiomers were assumed to be agonists of both CB1 and CB2 receptors, and the EC50 values of the (S)-enantiomers for the CB1 receptors were about five times lower than those of (R)-enantiomers. (R) MDMB-FUBICA was shown to function as an agonist of the CB2 receptor, but lacks CB1 receptor activity. To the best of our knowledge, this is the first report to show that the (R)-enantiomers of the carboxamide-type synthetic cannabinoids have the potency to activate CB1 and CB2 receptors. The findings presented here shed light on the pharmacological properties of these carboxamide-type synthetic cannabinoids in forensic cases.
Highlights
In recent years, several new psychoactive substances (NPS) have been newly identified from illicit drug products, one after another, and have been abused as legal alternatives to scheduled drugs [1]
Recently, carboxamide-type synthetic cannabinoids have been distributed globally as new psychoactive substances (NPS). Some of these compounds possess asymmetric carbon, which is derived from an amide moiety composed of amino acid derivatives. We synthesized both enantiomers of synthetic cannabinoids, N-(1-amino-3-methyl-1oxobutan-2-yl)-1-(2-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA 2-fluorobenzyl isomer), N-(1amino-1-oxo-3-phenylpropan-2-yl)-1-(cyclohexylmethyl)1H-indazole-3-carboxamide (APP-CHMINACA), ethyl [1(5-fluoropentyl)-1H-indazole-3-carbonyl]valinate (5FEMB-PINACA), ethyl [1-(4-fluorobenzyl)-1H-indazole-3carbonyl]valinate (EMB-FUBINACA), and methyl 2-[1(4-fluorobenzyl)-1H-indole-3-carboxamido]-3,3-dimethylbutanoate (MDMB-FUBICA), which were reported as NPS found in Europe from 2014 to 2015, to evaluate their activities as CB1/CB2 receptor agonists
Among the carboxamide-type synthetic cannabinoids, some compounds possess asymmetric carbon, which is derived from an amide moiety composed of amino acid derivatives
Summary
Several new psychoactive substances (NPS) have been newly identified from illicit drug products, one after another, and have been abused as legal alternatives to scheduled drugs [1]. Forensic cases of synthetic cannabinoid use have increased recently; the adverse effects of indazole-carboxamide-type synthetic cannabinoids, especially, present severe social problems [2]. Among the carboxamide-type synthetic cannabinoids, some compounds possess asymmetric carbon, which is derived from an amide moiety composed of amino acid derivatives (i.e., amides or esters of amino acids). These classes of compounds were first developed by Pfizer as potential therapeutic drugs; their patent only includes (S)-enantiomers, even though the structures of these compounds have chiral centers [8]. To evaluate their potency to activate CB1 and CB2 cannabinoid receptors
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