Center for Drug Discovery, RTI International, 3040 Cornwallis Road, Research Triangle Park, Durham, NC, 27709, USA,
Psychopharmacology (Berl). 2014 Oct;231(21):4135-44. doi: 10.1007/s00213-014-3557-7. Epub 2014 May 7.
Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT₂A) receptors.
This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects.
Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors.
Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT₂A, serotonin 1A (5-HT₁A), and 5-HT₂A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT₂A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT₂A activation.
All psychoactive tryptamines are 5-HT₂A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines.
合成致幻色胺，尤其是由亚历山大·舒尔金最初描述的那些，在美国继续被滥用。不同色胺产生的主观体验范围表明，除了在 5-羟色胺 2A（5-HT₂A）受体上的激动剂活性的既定作用外，它们的作用还涉及多种神经化学机制。
本研究评估了一系列合成色胺与生物胺神经递质转运体以及与致幻作用相关的 5-羟色胺（5-HT）受体亚型的相互作用。
在大鼠脑突触体中测定神经递质转运体活性。使用钙动员和 DiscoveRx PathHunter 测定法，在转染人受体的 HEK293、Gα16-CHO 和 CHOk1 细胞中测定受体活性。
在转运体摄取和释放测定中分析了 21 种色胺，并在 5-HT₂A、5-羟色胺 1A（5-HT₁A）和 5-HT₂Aβ-arrestin 功能测定中进行了分析。发现其中 8 种化合物具有 5-HT 释放活性。发现 13 种化合物是 5-HT 摄取抑制剂或无活性。所有色胺均为 5-HT₂A 激动剂，具有不同的效力和功效，但只有少数化合物为 5-HT1A 激动剂。大多数色胺通过 5-HT₂A 激活募集β-arrestin。
所有精神活性色胺均为 5-HT₂A 激动剂，但 5-HT 转运体（SERT）活性可能对某些化合物的药理学有重要贡献。体外转运体数据证实了释放剂和摄取抑制剂的结构-活性趋势，即释放剂往往是结构较小的化合物。有趣的是，发现两种叔胺是 SERT 的选择性底物，这消除了 5-HT 释放活性仅限于伯胺或仲胺的观点。
