Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093-0804, USA; Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr, San Diego, CA, 92161, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093-0804, USA.
Neuropharmacology. 2020 Aug 1;172:107856. doi: 10.1016/j.neuropharm.2019.107856. Epub 2019 Nov 19.
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
麦角酰二乙胺（LSD）是最有效的迷幻药之一。1-乙酰-LSD（ALD-52）是 LSD 的一种衍生物，其吲哚氮上有一个乙酰基，也会在人类中产生迷幻作用，其效力与 LSD 大致相同。最近，其他几种 1-酰基取代的 LSD 衍生物，包括 1-丙酰基-LSD（1P-LSD）和 1-丁酰基-LSD（1B-LSD），已作为设计药物出现。尽管这些化合物被认为是 LSD 的前体药物，但尚未有研究专门测试这一预测。本研究旨在填补关于 1-酰基取代 LSD 衍生物的药理作用和作用机制的信息空白。竞争性结合研究和钙动员测定用于评估 ALD-52、1P-LSD 和 1B-LSD 与 5-羟色胺 5-HT 受体亚型的相互作用。用 1B-LSD 进行受体组筛选，以评估其与其他潜在靶标的结合。在 C57BL/6J 小鼠中进行头部抽搐反应（HTR）研究，以评估体内激活 5-HT（被认为主要负责致幻作用的受体）的情况。最后，使用液相色谱/离子阱质谱（LC/MS）定量 Sprague-Dawley 大鼠血浆中 LSD 水平，该大鼠用 ALD-52 和 1P-LSD 处理。1-酰基取代将 LSD 对大多数单胺受体（包括 5-HT 部位）的亲和力降低了一个到两个数量级。尽管 LSD 作为 5-HT 亚型的激动剂起作用，但 ALD-52、1P-LSD 和 1B-LSD 在钙动员测定中具有弱效价或作为拮抗剂起作用。尽管 1-酰基取代对 5-HT 亲和力和效价有不利影响，但 1-酰基取代的 LSD 衍生物仍能以相对较高的效力在小鼠中引起头部抽搐。在大鼠皮下给予 ALD-52 和 1P-LSD 后，在血浆中检测到高浓度的 LSD，表明这些化合物在体内迅速有效地脱酰化。这些发现与 ALD-52、1P-LSD 和 1B-LSD 作为 LSD 前体药物的预测一致。本文是题为“血清素研究：跨越尺度和边界”的特刊的一部分。
