Identification of the synthetic cannabinoid N-(2-phenyl-propan-2-yl)-1-(4-cyanobutyl)-1H-indazole-3-carboxamide (CUMYL-4CN-BINACA) in a herbal mixture product

Ölmez, Nevin Arıkan; Kapucu, Hicran; Altun, Neslihan Çallı; Eren, Bülent

doi:10.1007/s11419-017-0372-y

Cited by 7 publications

(5 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…, geminal dimethylbenzyl) head group, as seen in 5F-CUMYL-P7AICA ( 7 ). Several cumyl-derived SCRAs were first reported in a patent from a New Zealand company in 2014. , Many cumyl-derived SCRAs have been identified as NPS, − and several of these have been associated with mass intoxications and other serious adverse events, including deaths. − Limited pharmacological and toxicological data are available for several cumyl-derived SCRAs, although these compounds typically exert potent cannabimimetic activity in vitro and in vivo . − Some of the earliest cumyl-derived SCRAs detected in NPS markets were CUMYL-PICA ( 9 , Figure ), CUMYL-PINACA ( 15 , Figure ), and CUMYL-BUTICA ( 10 , Figure ), all of which were initially detected in Slovenia in 2014 . More recently, cumyl-derived SCRAs featuring a cyclobutyl tail, such as CUMYL-CBMICA ( 13 , Figure ) and CUMYL-CBMINACA ( 19 , Figure ), were identified in several European countries from 2019 to 2020. ,, Taken together, these reports underscore the rapid structural evolution in the SCRA NPS marketplace and the dissemination of cumyl-derived SCRAs globally.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, SCRA manufacturers have produced analogues in which the indole core is replaced with a bioisosteric heteroaromatic system like indazole (e.g., ADB-BUTINACA, 6, Figures 1) or 7-azaindole (e.g., 5F-CUMYL-P7AICA, 7, Figure 1), or other alternative cores (e.g., an oxoindoline core like in, e.g., BZO-HEXOXIZID, Figure 1. Selected natural and synthetic agonists of cannabinoid receptors 1 and 2: Δ 9 -THC (1), CP-55,940 (2), JWH-018 (3), BB-22 (4), APICA (5), ADB-BUTINACA (6), CUMYL-5F-P7AICA (7), and BZO-HEXOXIZID (8). 8, Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA

Janssens

Ametovski

Sparkes

et al. 2022

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as new psychoactive substances. Effective monitoring and characterization of SCRAs are hindered by the rapid pace of structural evolution. Ahead of possible appearance on the illicit drug market, new SCRAs were synthesized to complete a systematic library of cumyl-indole-(e.g., CUMYL-CPrMICA, CUMYL-CPMICA) and cumyl-indazole-carboxamides (e.g., CUMYL-CPrMINACA, CUMYL-CPMINACA), encompassing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl tails. Comprehensive pharmacological characterization was performed with three assay formats, monitoring the recruitment of either wild-type or C-terminally truncated (βarr2d366) β-arrestin2 to the activated cannabinoid 1 receptor (CB 1 ) or monitoring G βγ -mediated membrane hyperpolarization. Altered compound characterization was observed when comparing derived potency (EC 50 ) and efficacy (E max ) values from both assays monitoring the same or a different signaling event, whereas ranges and ranking orders were similar. Structure−activity relationships (SAR) were assessed in threefold, resulting in the identification of the pendant tail as a critical pharmacophore, with the optimal chain length for CB 1 activation approximating an npentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activity of the SCRAs encompassing cyclic tails decreased with decreasing number of carbons forming the cyclic moiety, with CUMYL-CPrMICA showing the least CB 1 activity in all assay formats. The SARs were rationalized via molecular docking, demonstrating the importance of the optimal steric contribution of the hydrophobic tail. While SAR conclusions remained largely unchanged, the differential compound characterization by both similar and different assay designs emphasizes the importance of detailing specific assay characteristics to allow adequate interpretation of potencies and efficacies.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA

Janssens

Ametovski

Sparkes

et al. 2022

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Amino acid-derived esters and amides appended to an indole or indazole core, such as AMB-FUBINACA ( 6 ), are a prevalent class of potent SCRAs associated with adverse events including mass overdoses . Amides substituted with a geminal dimethylbenzyl (cumyl) group, such as CUMYL-4CN-BUTINACA ( 7 ), have appeared in recent years based on a 2014 patent disclosing this structural unit in a series of CB 1 agonists, − and medicinal chemistry techniques like scaffold hopping have been applied to generate 7-azaindole analogues like CUMYL-5F-P7AICA ( 8 ). − The pace of continuing structural evolution of SCRAs presents major challenges for scientists, health workers, law enforcement agents, and legislators. , …”

Section: Introductionmentioning

confidence: 99%

NNL-3: A Synthetic Intermediate or a New Class of Hydroxybenzotriazole Esters with Cannabinoid Receptor Activity?

Ametovski

Cairns

Grafinger

et al. 2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Synthetic cannabinoid receptor agonists (SCRAs) remain a prolific class of new psychoactive substances (NPS) and continue to expand rapidly. Despite the recent identification of hydroxybenzotriazole (HOBt) containing SCRAs in synthetic cannabis samples, there is currently no information regarding the pharmacological profile of these NPS with respect to human CB1 and CB2 receptors. In the current study, a series consisting of seven HOBt indole-, indazole-, and 7-azaindole-carboxylates bearing a range of N-alkyl substituents were synthesized and pharmacologically evaluated. Competitive binding assays at CB1 and CB2 demonstrated that all analogues except a 2-methyl-substituted derivative had low affinity for CB1 (K i = 3.80–43.7 μM) and CB2 (K i = 2.75–18.2 μM). A fluorometric functional assay revealed that 2-methylindole- and indole-derived HOBt carboxylates were potent and efficacious agonists of CB1 (EC50 = 12.0 and 63.7 nM; E max = 118 and 120%) and CB2 (EC50 = 10.9 and 321 nM; E max = 91 and 126%). All other analogues incorporating indazole and 7-azaindole cores and bearing a range of N1-substituents showed relatively low potency for CB1 and CB2. Additionally, a reporter assay monitoring β-arrestin 2 (βarr2) recruitment to the receptor revealed that the 2-methylindole example was the most potent and efficacious at CB1 (EC50 = 131 nM; E max = 724%) and the most potent at CB2 (EC50 = 38.2 nM; E max = 51%). As with the membrane potential assay, the indazole and other indole HOBt carboxylates were considerably less potent at both receptors, and analogues comprising a 7-azaindole core showed little activity. Taken together, these data suggest that NNL-3 demonstrates little CB1 receptor activity and is unlikely to be psychoactive in humans. NNL-3 is likely an unintended SCRA manufacturing byproduct. However, the synthesis of NNL-3 analogues proved simple and general, and some of these showed potent cannabimetic profiles in vitro, indicating that HOBt esters of this type may represent an emerging class of SCRA NPS.

show abstract

“…CUMYL-4CN-BINACA (1-(4-cyanobutyl)- N -(2-phenylpropan-2-yl)indazole-3-carboxamide) ( 1 ), also known as 4CN-CUMYL-BUTINACA, CUMYL-CYBINACA, and SGT-78, has been available as a synthetic cannabinoid receptor agonist (SCRA) and new psychoactive substance (NPS) in the European Union and elsewhere since late 2015, with more than 2,400 seizures reported by nine countries (European Monitoring Centre for Drugs and Drug Addiction, 2017; Arıkan Ölmez et al, 2018). CUMYL-4CN-BINACA has been detected in multiple forms, including liquids and powders, with a single seizure of 50 kg of powder intercepted by Spanish customs en route from China (European Monitoring Centre for Drugs and Drug Addiction, 2017).…”

Section: Introductionmentioning

confidence: 99%

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

et al. 2019

View full text Add to dashboard Cite

Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)- N -(2-phenylpropan-2-yl)indazole-3-carboxamide) is structurally related to potent, cumylamine-derived SCRAs such as 5F-CUMYL-PINACA, but is unusual due to a terminal aliphatic nitrile group not frequently encountered in SCRAs or pharmaceuticals. We report here that CUMYL-4CN-BINACA is a potent CB 1 receptor agonist ( K i = 2.6 nM; EC 50 = 0.58 nM) that produces pro-convulsant effects in mice at a lower dose than reported for any SCRA to date (0.3 mg/kg, i.p). Hypothermic and pro-convulsant effects in mice could be reduced or blocked, respectively, by pretreatment with CB 1 receptor antagonist SR141716, pointing to at least partial involvement of CB 1 receptors in vivo . Pretreatment with CB2 receptor antagonist AM-630 had no effect on pro-convulsant activity. The pro-convulsant properties and potency of CUMYL-4CN-BINACA may underpin the toxicity associated with this compound in humans.

show abstract

Identification of the synthetic cannabinoid N-(2-phenyl-propan-2-yl)-1-(4-cyanobutyl)-1H-indazole-3-carboxamide (CUMYL-4CN-BINACA) in a herbal mixture product

Cited by 7 publications

References 20 publications

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA

Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA

NNL-3: A Synthetic Intermediate or a New Class of Hydroxybenzotriazole Esters with Cannabinoid Receptor Activity?

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

Contact Info

Product

Resources

About