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Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays: Part I-Synthesis, analytical characterization, and binding affinity for human CB1 receptors

(2021) DRUG TESTING AND ANALYSIS. 13(7). p.1383-1401
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Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, pharmacological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical characterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl l-valinate (MMB), methyl l-tert-leucinate (MDMB), methyl l-phenylalaninate (MPP), l-valinamide (AB), l-tert-leucinamide (ADB), l-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB1 binding affinity (K-i = 0.17-39 nM), followed by indole- (K-i = 0.95-160 nM) and then 7-azaindole-derived SCRAs (K-i = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (K-i = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (K-i = 0.72-180 nM), and then phenylalanine derivatives (K-i = 2.5-271 nM). Adamantyl head groups (K-i = 8.8-59 nM) were suboptimal for binding, whereas the cumyl analogues consistently conferred high affinity (K-i = 0.62-36 nM). Finally, both butyl (K-i = 3.1-163 nM) and 4-cyanobutyl (K-i = 5.5-44 nM) tail groups were less favorable for CB1 binding than their corresponding 4-pentenyl counterparts (K-i = 0.72-25 nM).
Keywords
PHARMACOLOGICAL EVALUATION, POTENT, CONSTITUENTS, INDAZOLE, FUBINACA, INDOLE, DRUGS, 4en, ADB, cannabinoid, MDMB, PINACA

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MLA
Pike, Edward, et al. “Systematic Evaluation of a Panel of 30 Synthetic Cannabinoid Receptor Agonists Structurally Related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA Using a Combination of Binding and Different CB1 Receptor Activation Assays: Part I-Synthesis, Analytical Characterization, and Binding Affinity for Human CB1 Receptors.” DRUG TESTING AND ANALYSIS, vol. 13, no. 7, 2021, pp. 1383–401, doi:10.1002/dta.3037.
APA
Pike, E., Grafinger, K., Cannaert, A., Ametovski, A., Luo, J. L., Sparkes, E., … Banister, S. D. (2021). Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays: Part I-Synthesis, analytical characterization, and binding affinity for human CB1 receptors. DRUG TESTING AND ANALYSIS, 13(7), 1383–1401. https://doi.org/10.1002/dta.3037
Chicago author-date
Pike, Edward, Katharina Grafinger, Annelies Cannaert, Adam Ametovski, Jia Lin Luo, Eric Sparkes, Elizabeth A. Cairns, et al. 2021. “Systematic Evaluation of a Panel of 30 Synthetic Cannabinoid Receptor Agonists Structurally Related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA Using a Combination of Binding and Different CB1 Receptor Activation Assays: Part I-Synthesis, Analytical Characterization, and Binding Affinity for Human CB1 Receptors.” DRUG TESTING AND ANALYSIS 13 (7): 1383–1401. https://doi.org/10.1002/dta.3037.
Chicago author-date (all authors)
Pike, Edward, Katharina Grafinger, Annelies Cannaert, Adam Ametovski, Jia Lin Luo, Eric Sparkes, Elizabeth A. Cairns, Ross Ellison, Roy Gerona, Christophe Stove, Volker Auwaerter, and Samuel D. Banister. 2021. “Systematic Evaluation of a Panel of 30 Synthetic Cannabinoid Receptor Agonists Structurally Related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA Using a Combination of Binding and Different CB1 Receptor Activation Assays: Part I-Synthesis, Analytical Characterization, and Binding Affinity for Human CB1 Receptors.” DRUG TESTING AND ANALYSIS 13 (7): 1383–1401. doi:10.1002/dta.3037.
Vancouver
1.
Pike E, Grafinger K, Cannaert A, Ametovski A, Luo JL, Sparkes E, et al. Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays: Part I-Synthesis, analytical characterization, and binding affinity for human CB1 receptors. DRUG TESTING AND ANALYSIS. 2021;13(7):1383–401.
IEEE
[1]
E. Pike et al., “Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays: Part I-Synthesis, analytical characterization, and binding affinity for human CB1 receptors,” DRUG TESTING AND ANALYSIS, vol. 13, no. 7, pp. 1383–1401, 2021.
@article{8722230,
  abstract     = {{Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, pharmacological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical characterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl l-valinate (MMB), methyl l-tert-leucinate (MDMB), methyl l-phenylalaninate (MPP), l-valinamide (AB), l-tert-leucinamide (ADB), l-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB1 binding affinity (K-i = 0.17-39 nM), followed by indole- (K-i = 0.95-160 nM) and then 7-azaindole-derived SCRAs (K-i = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (K-i = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (K-i = 0.72-180 nM), and then phenylalanine derivatives (K-i = 2.5-271 nM). Adamantyl head groups (K-i = 8.8-59 nM) were suboptimal for binding, whereas the cumyl analogues consistently conferred high affinity (K-i = 0.62-36 nM). Finally, both butyl (K-i = 3.1-163 nM) and 4-cyanobutyl (K-i = 5.5-44 nM) tail groups were less favorable for CB1 binding than their corresponding 4-pentenyl counterparts (K-i = 0.72-25 nM).}},
  author       = {{Pike, Edward and Grafinger, Katharina and Cannaert, Annelies and Ametovski, Adam and Luo, Jia Lin and Sparkes, Eric and Cairns, Elizabeth A. and Ellison, Ross and Gerona, Roy and Stove, Christophe and Auwaerter, Volker and Banister, Samuel D.}},
  issn         = {{1942-7603}},
  journal      = {{DRUG TESTING AND ANALYSIS}},
  keywords     = {{PHARMACOLOGICAL EVALUATION,POTENT,CONSTITUENTS,INDAZOLE,FUBINACA,INDOLE,DRUGS,4en,ADB,cannabinoid,MDMB,PINACA}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1383--1401}},
  title        = {{Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays: Part I-Synthesis, analytical characterization, and binding affinity for human CB1 receptors}},
  url          = {{http://dx.doi.org/10.1002/dta.3037}},
  volume       = {{13}},
  year         = {{2021}},
}

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