Evaluation of carboxamide-type synthetic cannabinoids as CB(1)/CB(2) receptor agonists: difference between the enantiomers

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 CB(1)/CB(2) receptor agonists. With the exception of (R) MDMB-FUBICA, all of the tested enantiomers were assumed to be agonists of both CB(1) and CB(2) receptors, and the EC(50) values of the (S)-enantiomers for the CB(1) receptors were about five times lower than those of (R)-enantiomers. (R) MDMB-FUBICA was shown to function as an agonist of the CB(2) receptor, but lacks CB(1) 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 CB(1) and CB(2) receptors. The findings presented here shed light on the pharmacological properties of these carboxamide-type synthetic cannabinoids in forensic cases.