Products Cited in Publications Worldwide 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

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

Pike, Edward; Grafinger, Katharina Elisabeth; Cannaert, Annelies; Ametovski, Adam; Luo, Jia Lin; Sparkes, Eric; Cairns, Elizabeth A.; Ellison, Ross; Gerona, Roy; Stove, Christophe P.; Auwaerter, Volker; Banister, Samuel D.

DOI: PMID:

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances. In this first of a three-part series, author describe the synthesis, anal. 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, Bu, or 4-cyanobutyl tail and a Me L-valinate (MMB), Me L-tert-leucinate (MDMB), Me 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 (Ki = 0.17-39 nM), followed by indole- (Ki = 0.95-160 nM) and then 7-azaindole-derived SCRAs (Ki = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and Me esters (Ki = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (Ki = 0.72-180 nM), and then phenylalanine derivatives (Ki = 2.5-271 nM). Adamantyl head groups (Ki = 8.8-59 nM) were suboptimal for binding, whereas the cumyl analogs consistently conferred high affinity (Ki = 0.62-36 nM). Finally, both Bu (Ki = 3.1-163 nM) and 4-cyanobutyl (Ki = 5.5-44 nM) tail groups were less favorable for CB1 binding than their corresponding 4-pentenyl counterparts (Ki = 0.72-25 nM).

Keywords

4en ; ADB ; MDMB ; PINACA ; cannabinoid

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5-Bromo-1-pentene

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