FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice.
FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice.
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FPT 是一种 2-Aminotetralin，是一种有效的血清素 5-HT1A、5-HT1B 和 5-HT1D 受体激动剂，可调节成年 Fmr1 敲除小鼠的皮质脑电图活动。
DOI：
10.1021/acschemneuro.2c00574
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发表时间：
2022
影响因子：
5
通讯作者：
Canal,ClintonE
中科院分区：
文献类型：
--
作者：
Saraf,TanishkaS;McGlynn,RyanP;Bhatavdekar,OmkarM;Booth,RaymondG;Canal,ClintonE
脆性X综合征(FXS)是一种单基因神经发育障碍，目前还没有批准的药物。脑电(EEG)研究显示，FXS患者的静息状态皮层脑电谱发生了变化，如伽马频段功率增加，FXS的Fmr1基因敲除模型中也观察到了这些变化，为药物开发提供了可能的生物标志物。编码5-羟色胺受体(5-HTR)的基因，包括5-HT1A、5-HT1B和5-HT1DR，在FXS中差异表达，为研究它们作为药物治疗靶点提供了理论基础。此前，我们报道了口服活性2-氨基四氢呋喃(S)-5-(2‘-氟苯基)-N，N-dimethyl-1，2，3，4-tetrahydronaphthalen-2-amine的药理活性和临床前神经治疗作用。FPT是一种有效的(低NM)、高效的5-HT1ARs部分激动剂和有效的、低效的5-HT7Rs部分激动剂。在这里，我们报告了新的观察结果，即FPT在人的5-HT1带和5-HT1DR上也具有强大而有效的激动剂活性。FPT在5-HT1和5-HT1DR的Ki值为<；5 nM，但在5-HT1FR没有活性(>；10μMkI)。我们在自由活动小鼠、成年Fmr1基因敲除小鼠和正常小鼠皮下注射FPT(5.6 mg/kg，皮下注射)，以检测其对体感皮层和听觉皮质上记录的脑电的影响。与之前的报告一致，我们从左侧躯体感觉皮质(LSSC)上方的记录中观察到，未经治疗或经赋形剂治疗的雄性和雌性Fmr1基因敲除小鼠的相对伽马功率显著增加。此外，我们还观察了性别对脑电功率的影响。FPT不能消除LSSC的相对伽马功率的基因型差异。然而，FPT显著降低了LSSC和听觉皮质的相对阿尔法功率，对Fmr1KO小鼠的影响更为明显。同样，FPT降低了右侧SSC的相对阿尔法功率，但仅在Fmr1基因敲除小鼠中降低。FPT还增加了相对增量功率，对Fmr1KO小鼠的影响更为明显，并导致相对β功率小幅但显著增加。FPT对皮质脑电的明显影响类似于FDA批准的某些精神药物(包括巴氯芬、别孕酮和氯氮平)所引起的影响。这些结果促进了对FPT的药理和神经生理学作用的理解。
There are no approved medicines for fragile X syndrome (FXS), a monogenic, neurodevelopmental disorder. Electroencephalogram (EEG) studies show alterations in resting-state cortical EEG spectra, such as increased gamma-band power, in patients with FXS that are also observed inFmr1knockout models of FXS, offering putative biomarkers for drug discovery. Genes encoding serotonin receptors (5-HTRs), including 5-HT1A, 5-HT1B, and 5-HT1DRs, are differentially expressed in FXS, providing a rationale for investigating them as pharmacotherapeutic targets. Previously we reported pharmacological activity and preclinical neurotherapeutic effects inFmr1knockout mice of an orally active 2-aminotetralin, (S)-5-(2′-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HT1ARs and a potent, low-efficacy partial agonist at 5-HT7Rs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT1Band 5-HT1DRs. FPT’sKivalues at 5-HT1Band 5-HT1DRs were <5 nM, but it had nil activity (>10 μMKi) at 5-HT1FRs. We tested the effects of FPT (5.6 mg/kg, subcutaneous) on EEG recorded above the somatosensory and auditory cortices in freely moving, adultFmr1knockout and control mice. Consistent with previous reports, we observed significantly increased relative gamma power in untreated or vehicle-treated male and femaleFmr1knockout mice from recordings above the left somatosensory cortex (LSSC). In addition, we observed sex effects on EEG power. FPT did not eliminate the genotype difference in relative gamma power from the LSSC. FPT, however, robustly decreased relative alpha power in the LSSC and auditory cortex, with more pronounced effects inFmr1KO mice. Similarly, FPT decreased relative alpha power in the right SSC but only inFmr1knockout mice. FPT also increased relative delta power, with more pronounced effects inFmr1KO mice and caused small but significant increases in relative beta power. Distinct impacts of FPT on cortical EEG were like effects caused by certain FDA-approved psychotropic medications (including baclofen, allopregnanolone, and clozapine). These results advance the understanding of FPT’s pharmacological and neurophysiological effects.
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影响因子：
11.2
作者：
O. Press;A. Farr;Borroz Ki;S. Anderson;P. Martin
通讯作者：
O. Press;A. Farr;Borroz Ki;S. Anderson;P. Martin
高剂量放射性标记抗体治疗淋巴瘤。
影响因子：
11.2
作者：
Bernstein,ID;Eary,JF;Badger,CC;Press,OW;Appelbaum,FR;Martin,PJ;Krohn,KA;Nelp,WB;Porter,B;Fisher,D
通讯作者：
Fisher,D
影响实验性肝癌中 131 I-抗铁蛋白肿瘤定位的变量
DOI：
--
发表时间：
1984
期刊：
American Journal of Clinical Oncology
影响因子：
--
作者：
R. Rostock;K. Kopher;J. Klein;S. Order
通讯作者：
S. Order
B 细胞淋巴瘤的影像学和治疗。
DOI：
--
发表时间：
1990
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Eary,JF;Press,OW;Badger,CC;Durack,LD;Richter,KY;Addison,SJ;Krohn,KA;Fisher,DR;Porter,BA;Williams,DL
通讯作者：
Williams,DL
实验性肝癌中影响 131I-抗铁蛋白肿瘤定位的分布和生理因素。
DOI：
10.1016/0360-3016(84)90188-3
发表时间：
1984
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
R. Rostock;J. Klein;P. Leichner;S. Order
通讯作者：
S. Order