Abstract
MMB022 (methyl 3-methyl-2-[1-(pent-4-en-1-yl)-1H-indole-3-carboxamido]butanoate) is a new synthetic cannabinoid with an alkene at the pentenyl side chain, a rare functional group for synthetic cannabinoids. Metabolite identification is an important step for the detection of synthetic cannabinoids in humans, since they are generally extensively metabolized. The aims of the study were to tentatively identify in vitro phase I metabolites, to confirm major metabolites using synthesized metabolites, to examine metabolic pathways thoroughly, to study metabolic stability and to suggest metabolites appropriate for urine screening. MMB022 and its synthesized metabolites were incubated with human liver microsomes (HLM) and the supernatants were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Sixteen metabolites were identified, which were generated via dehydrogenation, dihydrodiol formation, ester hydrolysis, hydroxylation, and combinations thereof. A major biotransformation of the alkene at the pentenyl side chain was confirmed to be dihydrodiol formation. The major metabolites were ester hydrolysis (M15) and dihydrodiol (M8) metabolites, whereas the metabolite derived from the combination of ester hydrolysis and dihydrodiol (M5) was the fourth most abundant metabolite. The metabolic pathways were investigated using synthesized metabolites and revealed that M5 is an end product of the pathways, indicating that it might become a more abundant metabolite in vivo depending on the rate of metabolism in humans. The major pathway of MMB022 to M5 was determined to be via M8 formation. Intrinsic clearance of MMB022 was determined to be 296 mL/min/kg and t1/2 was 2.1 min, indicating a low metabolic stability. M15, M8, and potentially M5 are suggested as suitable urinary targets.
Highlights
The emergence and prevalence of new psychoactive substances (NPS) is still a continuing problem in Europe.[1,2] NPS can pose a serious health risk to users due to the unknown nature of the potency and toxicity of the newly emerged drugs
Identification of major metabolites prior to drug testing becomes indispensable to prove the use of NPS by detection of metabolites in biological matrices
It has been reported as a minor component of products with other NPS, analogs, including N(4-pentenyl)-JWH-122,10 N-(4-pentenyl)-XLR-11 ( known as N-(4-pentenyl)-UR-144),[11] and N-(4-pentenyl)-AKB-48.12 the first cannabinoids seen as the main components were JWH0222 and MDMB-4en-PINACA9 and not until the latter became prevalent in 2019 did they receive much attention
Summary
The emergence and prevalence of new psychoactive substances (NPS) is still a continuing problem in Europe.[1,2] NPS can pose a serious health risk to users due to the unknown nature of the potency and toxicity of the newly emerged drugs. A carbon–carbon double bond on the pentyl side chain is a rare modification among synthetic cannabinoids It has been reported as a minor component of products with other NPS, analogs, including N(4-pentenyl)-JWH-122,10 N-(4-pentenyl)-XLR-11 ( known as N-(4-pentenyl)-UR-144),[11] and N-(4-pentenyl)-AKB-48.12 the first cannabinoids seen as the main components were JWH0222 and MDMB-4en-PINACA9 and not until the latter became prevalent in 2019 did they receive much attention. Due to the structural similarity between MMB022 and MDMB-4en-PINACA, dihydrodiol formation from the alkene and ester hydrolysis of the valinate methyl ester can be expected to be the major metabolic pathways for MMB022. Unambiguous identification of the dihydrodiol formation is necessary to confirm the major biotransformation of the alkene in the pentenyl side chain of synthetic cannabinoids. The metabolic stability was investigated and suitable urinary marker metabolites were suggested
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