Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
ACS Chem Neurosci. 2023 Jul 19;14(14):2527-2536. doi: 10.1021/acschemneuro.3c00156. Epub 2023 Jul 5.
α-Pyrrolidinohexiophenone (α-PHP) is the one-carbon unit α-extended homolog of the better-known and widely abused synthetic cathinone central stimulant α-PVP ("flakka"); both are now U.S. Schedule I controlled substances. Structurally, α-PVP and α-PHP possess a common terminal N-pyrrolidine moiety and differ only with respect to the length of their α-alkyl chain. Using a synaptosomal assay, we previously reported that α-PHP is at least as potent as α-PVP as a dopamine transporter (DAT) reuptake inhibitor. A systematic structure-activity study of synthetic cathinones (e.g., α-PHP) as DAT reuptake inhibitors (i.e., transport blockers), a mechanism thought responsible for their abuse liability, has yet to be conducted. Here, we examined a series of 4-substituted α-PHP analogues and found that, with one exception, all behaved as relatively (28- to >300-fold) selective DAT versus serotonin transporter (SERT) reuptake inhibitors with DAT inhibition potencies of most falling within a very narrow (i.e., <3-fold) range. The 4-CF analogue of α-PHP was a confirmed "outlier" in that it was at least 80-fold less potent than the other analogues and displayed reduced (i.e., no) DAT vs SERT selectivity. Consideration of various physicochemical properties of the CF group, relative to that of the other substituents involved here, provided relatively little insight. Unlike with DAT-releasing agents, as previously reported by us, a QSAR study was precluded because of the limited range of empirical results (with the exception of the 4-CF analogue) for DAT reuptake inhibition.
α- 吡咯烷己基酮（α-PHP）是更为人熟知且被广泛滥用的合成卡西酮中枢兴奋剂 α-PVP（“flakka”）的一碳单元 α- 延伸同系物；两者现在均被列为美国管制物质附表 I。在结构上，α-PVP 和 α-PHP 具有共同的末端 N-吡咯烷部分，仅在其 α- 烷基链的长度上有所不同。我们之前使用突触小体测定法报告称，α-PHP 作为多巴胺转运体（DAT）再摄取抑制剂的效力至少与 α-PVP 一样强。作为 DAT 再摄取抑制剂（即转运体阻滞剂）的合成卡西酮（例如 α-PHP）的系统结构活性研究，一种被认为与其滥用倾向有关的机制，尚未进行。在这里，我们研究了一系列 4-取代的 α-PHP 类似物，发现除了一个例外，所有类似物均表现出相对（28 至 >300 倍）对 DAT 与 5-羟色胺转运体（SERT）再摄取的选择性，其中大多数 DAT 抑制作用的强度都非常接近（即<3 倍）。α-PHP 的 4-CF 类似物是一个被确认的“异常值”，因为它的效力比其他类似物至少低 80 倍，并且显示出降低（即没有）的 DAT 与 SERT 的选择性。考虑到 CF 基团相对于这里涉及的其他取代基的各种物理化学性质，相对没有提供太多的见解。与我们之前报道的 DAT 释放剂不同，由于 DAT 再摄取抑制的经验结果范围有限（除了 4-CF 类似物之外），因此排除了 QSAR 研究。
