Schoeder Clara T, Hess Cornelius, Madea Burkhard, Meiler Jens, Müller Christa E
1PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
3Research Training Group 1873, University of Bonn, 53127 Bonn, Germany.
Forensic Toxicol. 2018;36(2):385-403. doi: 10.1007/s11419-018-0415-z. Epub 2018 Apr 26.
In the present study we characterized a series of synthetic cannabinoids containing various heterocyclic scaffolds that had been identified as constituents of "Spice", a preparation sold on the illicit drug market. All compounds were further investigated as potential ligands of the orphan receptors GPR18 and GPR55 that interact with some cannabinoids.
The compounds were studied in radioligand binding assays to determine their affinity for human cannabinoid CB and CB receptors expressed in CHO cells, and in cAMP accumulation assays to study their functionality.
Structure-activity relationships were analyzed. The most potent CB receptor agonist of the present series MDMB-FUBINACA () ( = 98.5 pM) was docked into the human CB receptor structure, and a plausible binding mode was identified showing high similarity with that of the co-crystallized THC derivatives. MDMB-CHMCZCA () displayed a unique profile acting as a full agonist at the CB receptor subtype, but blocking the CB receptor completely. Only a few weakly potent antagonists of GPR18 and GPR55 were identified, and thus all compounds showed high CB receptor selectivity, mostly interacting with both subtypes, CB and CB.
These results will be useful to assess the compounds' toxicological risks and to guide legislation. Further studies on are warranted.
在本研究中，我们对一系列含有各种杂环骨架的合成大麻素进行了表征，这些合成大麻素已被确定为非法毒品市场上出售的一种名为“香料”的制剂的成分。所有化合物都作为孤儿受体GPR18和GPR55的潜在配体进行了进一步研究，这两种受体与某些大麻素相互作用。
在放射性配体结合试验中研究这些化合物，以确定它们对CHO细胞中表达的人大麻素CB和CB受体的亲和力，并在cAMP积累试验中研究它们的功能。
分析了构效关系。本系列中最有效的CB受体激动剂MDMB - FUBINACA（）（= 98.5 pM）被对接至人CB受体结构中，并确定了一种似是而非的结合模式，该模式与共结晶的THC衍生物的结合模式高度相似。MDMB - CHMCZCA（）表现出独特的特性，在CB受体亚型上作为完全激动剂起作用，但完全阻断CB受体。仅鉴定出少数几种对GPR18和GPR55的低效拮抗剂，因此所有化合物均显示出高CB受体选择性，大多与CB和CB两种亚型相互作用。
这些结果将有助于评估这些化合物的毒理学风险并指导立法。有必要对进行进一步研究。
