Abstract：
Cultivation of industrial low-Δ9-tetrahydrocannabinol (Δ9-THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants-potentially located in a legal loophole-has led to a diversification of cannabis recreational drug markets. \'Hemp-compliant\', \'hemp-derived\' and \'semisynthetic\' cannabinoid products are emerging and being advertised as (legal) alternatives for Δ9-THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB1 cannabinoid receptor with a β-arrestin2 recruitment bioassay (picomolar-micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB1 activation than Δ9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure-activity relationships were assessed for Δ9-THC and Δ8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Δ7-THC, Δ10-THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ9-THC products.
摘要：
工业低Δ9-四氢大麻酚（Δ9-THC）大麻的种植导致了富含大麻二酚（CBD）的产品供过于求。事实上，植物大麻素，包括CBD,可以用作合成生产一系列THC变体的前体-可能位于法律漏洞中-导致大麻娱乐性药物市场的多样化。\'符合大麻要求\',“大麻衍生”和“半合成”大麻素产品正在兴起，并被宣传为Δ9-THC的（合法）替代品。这项研究包括一大群(n=30)THC异构体，同源物,以及可能通过半合成程序衍生的类似物。作为这些化合物滥用潜力的代表，我们通过β-arrestin2募集生物测定法(皮摩尔-微摩尔浓度)评估了它们激活CB1大麻素受体的潜力.多个THC同系物（四氢大麻酚，四氢甘蓝,THCP；四氢大麻酚-C8，THC-C8）和THC类似物（六氢大麻酚，HHC；六氢大麻酚，HHCP）被鉴定为显示出比Δ9-THC更高的CB1激活潜力，基于更高的疗效（Emax）或更高的效力（EC50）。评估包含细长烷基链的Δ9-THC和Δ8-THC同系物的结构-活性关系。此外,对于各种THC异构体，建立了CB1活性的立体异构体特异性差异（Δ7-THC，Δ10-THC)和类似物(HHC，HHCP）。对缉获的药物材料中9（S）-HHC和9（R）-HHC差向异构体的相对丰度的评估揭示了批次之间不同的差向异构体组成。活性较低的9(S)-HHC差向异构体的丰度增加经验上导致效力降低，但对所得非对映异构体混合物持续有效。总之,半合成大麻素的监测是鼓励剂量和立体异构体的相对组成可以影响这些药物的潜在危害,相对于Δ9-THC产品。
