Jensen Anders A, McCorvy John D, Leth-Petersen Sebastian, Bundgaard Christoffer, Liebscher Gudrun, Kenakin Terry P, Bräuner-Osborne Hans, Kehler Jan, Kristensen Jesper Langgaard
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.A.J., S.L-P., G.L., H.B.-O., J.L.K.); Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.D.M., T.P.K.); and Department of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark (C.B., J.K.).
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.A.J., S.L-P., G.L., H.B.-O., J.L.K.); Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.D.M., T.P.K.); and Department of Discovery Chemistry and DMPK, H. Lundbeck A/S, Valby, Denmark (C.B., J.K.)
J Pharmacol Exp Ther. 2017 Jun;361(3):441-453. doi: 10.1124/jpet.117.239905. Epub 2017 Mar 30.
Therapeutic interest in augmentation of 5-hydroxytryptamine (5-HT) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT receptor agonist -2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT, 5-HT, and 5-HT receptors and investigated the pharmacokinetic properties of the compound. 25CN-NBOH displayed robust 5-HT selectivity in [H]ketanserin/[H]mesulergine, [H]lysergic acid diethylamide and [H]Cimbi-36 binding assays (/ ratio range of 52-81; / ratio of 37). Moreover, in inositol phosphate and intracellular Ca mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT/5-HT selectivities and 54-fold 5-HT/5-HT selectivity as measured by Δlog(/EC) values. In an off-target screening 25CN-NBOH (10 M) displayed either substantially weaker activity or inactivity at a plethora of other receptors, transporters, and kinases. In a toxicological screening, 25CN-NBOH (100 M) displayed a benign acute cellular toxicological profile. 25CN-NBOH displayed high in vitro permeability (P = 29 × 10 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.
迷幻药物在治疗各种精神疾病方面的有效性，重新引发了人们对增强5-羟色胺（5-HT）受体信号传导的治疗兴趣。在本研究中，我们进一步表征了最近开发的5-HT受体激动剂-2-羟基苄基）-2,5-二甲氧基-4-氰基苯乙胺（25CN-NBOH）及其三种结构类似物在重组5-HT、5-HT和5-HT受体上的药理学特性，并研究了该化合物的药代动力学特性。在[H]酮色林/[H]美舒麦角、[H]麦角酸二乙酰胺和[H]Cimbi-36结合试验中，25CN-NBOH表现出强大的5-HT选择性（/比值范围为52-81；/比值为37）。此外，在肌醇磷酸和细胞内钙动员试验中，通过Δlog（/EC）值测量，25CN-NBOH表现出30至180倍的5-HT/5-HT选择性和54倍的5-HT/5-HT选择性。在脱靶筛选中，25CN-NBOH（10 M）在大量其他受体、转运体和激酶上表现出显著较弱的活性或无活性。在毒理学筛选中，25CN-NBOH（100 M）表现出良性的急性细胞毒理学特征。在传统的细胞转运屏障模型中，25CN-NBOH表现出高体外渗透性（P = 29 × 10 cm/s）和低P-糖蛋白介导的外排。在体内，给C57BL/6小鼠皮下注射25CN-NBOH（3 mg/kg）后15分钟内，血浆和脑中游离（未结合）化合物的浓度约为200 nM，进一步证明25CN-NBOH能迅速穿透血脑屏障且不会发生显著外排。总之，与（±）-2,5-二甲氧基-4-碘苯丙胺（DOI）相比，25CN-NBOH似乎是一种更优越的选择性且能穿透脑屏障的5-HT受体激动剂，因此我们认为该化合物可能是未来研究该受体介导的生理功能的有价值工具。
