Pike Edward, Grafinger Katharina Elisabeth, Cannaert Annelies, Ametovski Adam, Luo Jia Lin, Sparkes Eric, Cairns Elizabeth A, Ellison Ross, Gerona Roy, Stove Christophe P, Auwärter Volker, Banister Samuel D
The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, Australia.
School of Chemistry, The University of Sydney, Sydney, New South Wales, Australia.
Drug Test Anal. 2021 Jul;13(7):1383-1401. doi: 10.1002/dta.3037. Epub 2021 May 6.
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 CB binding affinity (K = 0.17-39 nM), followed by indole- (K = 0.95-160 nM) and then 7-azaindole-derived SCRAs (K = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (K = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (K = 0.72-180 nM), and then phenylalanine derivatives (K = 2.5-271 nM). Adamantyl head groups (K = 8.8-59 nM) were suboptimal for binding, whereas the cumyl analogues consistently conferred high affinity (K = 0.62-36 nM). Finally, both butyl (K = 3.1-163 nM) and 4-cyanobutyl (K = 5.5-44 nM) tail groups were less favorable for CB binding than their corresponding 4-pentenyl counterparts (K = 0.72-25 nM).
合成大麻素受体激动剂（SCRAs）是新型精神活性物质（NPS）中数量最多、结构多样性最高的类别之一。尽管如此，在毒品市场上发现一种新的SCRAs后，往往缺乏药理学数据。在这个由三部分组成的系列文章的第一篇中，我们描述了一个主动生成的、系统的包含30种与MMB-4en-PICA、MDMB-4en-PINACA、ADB-4en-PINACA和MMB-4CN-BUTINACA相关的吲哚、吲唑和7-氮杂吲哚SCRAs文库的合成、分析表征和结合亲和力，这些化合物具有4-戊烯基（4en-P）、丁基（B/BUT）或4-氰基丁基（4CN-B/BUT）尾部以及L-缬氨酸甲酯（MMB）、L-叔亮氨酸甲酯（MDMB）、L-苯丙氨酸甲酯（MPP）、L-缬氨酰胺（AB）、L-叔亮氨酰胺（ADB）、L-苯丙氨酰胺（APP）、金刚烷基（A）或枯基头部基团。竞争性放射性配体结合试验表明，吲唑核心赋予了最高的CB结合亲和力（K = 0.17 - 39 nM），其次是吲哚类（K = 0.95 - 160 nM），然后是7-氮杂吲哚衍生的SCRAs（K = 5.4 - 271 nM）。头部基团的变化对结合的影响最大，叔亮氨酸酰胺和甲酯（K = 0.17 - 14 nM）通常表现出最大的亲和力，其次是缬氨酸衍生物（K = 0.72 - 180 nM），然后是苯丙氨酸衍生物（K = 2.5 - 271 nM）。金刚烷基头部基团（K = 8.8 - 59 nM）结合效果欠佳，而枯基类似物始终具有高亲和力（K = 0.62 - 36 nM）。最后，丁基（K = 3.1 - 163 nM）和4-氰基丁基（K = 5.5 - 44 nM）尾部基团对CB结合的有利程度低于其相应的4-戊烯基对应物（K = 0.72 - 25 nM）。
