Glatfelter Grant C, Clark Allison A, Cavalco Natalie G, Landavazo Antonio, Partilla John S, Naeem Marilyn, Golen James A, Chadeayne Andrew R, Manke David R, Blough Bruce E, McCorvy John D, Baumann Michael H
Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
ACS Chem Neurosci. 2024 Dec 18;15(24):4458-4477. doi: 10.1021/acschemneuro.4c00513. Epub 2024 Dec 5.
5-methoxy-,-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its -alkyl, -allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT) and 1A receptors (5-HT), and 3) to examine the influence of 5-HT on 5-HT-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT and 5-HT. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED range = 0.2-1.8 mg/kg) and maximal effects ( range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED range = 3.2-20.6 mg/kg). 5-HT antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT antagonist pretreatment enhanced HTRs. In general, ,-dialkyl and -isopropyl derivatives displayed HTR activity, while the -methyl, -ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT unmasked latent HTR activity for the -ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT agonist activity can dampen 5-HT-mediated HTRs. Suppression of 5-HT-mediated HTRs by 5-HT only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT agonism in modulating acute psychoactive effects of 5-HT agonists.
5-甲氧基-N，N-二甲基色胺（5-MeO-DMT）类似物被用作消遣性药物，但它们也正被开发为潜在药物，因此有必要对其药理学进行进一步研究。在此，我们研究了5-MeO-DMT及其几种N-烷基、N-烯丙基和2-甲基类似物的神经药理学，主要有三个目的：1）确定这些化合物的体外受体谱；2）表征其在5-羟色胺（5-HT）2A受体（5-HT2A）和5-HT1A受体（5-HT1A）上的体外功能活性；3）在小鼠头部抽搐反应（HTR）模型中研究5-HT2A对5-HT介导的致幻样效应的影响。体外受体结合和功能测定表明，所有5-MeO-DMT类似物都以高亲和力结合并激活多个靶点（如5-HT受体亚型、α肾上腺素能受体），包括对5-HT2A和5-HT1A的强效作用。在C57Bl/6J小鼠中，皮下注射这些类似物会诱导出不同效力（ED范围=0.2-1.8毫克/千克）和最大效应（范围=20-60次HTR/30分钟）的HTR，同时在较高剂量（ED范围=3.2-20.6毫克/千克）时会诱导体温过低和运动减少。5-HT2A拮抗剂预处理可阻断药物诱导的HTR，而5-HT1A拮抗剂预处理则增强HTR。一般来说，N，N-二烷基和N-异丙基衍生物表现出HTR活性，而N-甲基、N-乙基和2-甲基类似物则没有。重要的是，阻断5-HT2A可揭示N-乙基类似物的潜在HTR活性，并显著增加其他HTR活性化合物的最大反应（40-90次HTR/30分钟），这支持了5-HT2A激动剂活性可抑制5-HT介导的HTR的观点。仅在高剂量5-MeO-DMT后，5-HT1A才会抑制5-HT介导的HTR，这表明其他受体参与了致幻样效应的调节。总体而言，我们的研究结果提供了有关5-MeO-DMT类似物的受体靶点谱、诱导致幻样效应的构效关系以及5-HT2A激动作用在调节5-HT激动剂急性精神活性效应中的关键作用的关键信息。
