Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile.
Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile.
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2-(4-氟苯氧基)-2-苯基乙基哌嗪的合成和生物学评价作为血清素选择性再摄取抑制剂，具有潜在改善不良反应的特征。
DOI：
10.1016/j.bmc.2003.12.021
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发表时间：
2004
影响因子：
3.5
通讯作者：
K. Pinney
中科院分区：
文献类型：
--
作者：
J. Dorsey;M. G. Miranda;N. Cozzi;K. Pinney
三种新的2-(4-氟苯氧基)-2-苯基-乙基哌嗪、1-(3-氯苯基)-4-[2-(4-氟苯氧基)-2-苯基乙基]-哌嗪7、1-[2-(4-氟苯氧基)-2-苯基乙基]-4-(2-甲氧基苯基)-哌嗪8和1-[2-(4-氟苯氧基)-2-苯基乙基]-4-(3-三氟甲基苯基)-哌嗪 9 以强效抗抑郁药氟西汀为模型，并与几种功能化哌嗪偶联，通过化学合成方法制备为选择性血清素再摄取抑制剂 (SSRI)，可能会改善不良反应。典型的 SSRIs 虽然在治疗抑郁症方面非常有效，但仍然面临着性功能障碍的麻烦副作用。许多药物（尤其是哌嗪类药物）已被用于逆转 SSRI 引起的性功能障碍，通过将氟西汀同系物与逆转剂的药效团偶联来开发改进的 SSRI 的证据有希望。初步数据表明，盐酸盐 (HCl) 10、11 和 12 均在血清素再摄取转运蛋白 (SERT) 位点上表现出单位点结合。然而，这三种化合物的效力均远低于典型的 SSRI，对 SERT 具有微摩尔 (μM) 亲和力，IC50 值分别为 1.45 μM、3.27 μM 和 9.56 μM。在就每种化合物用作无性副作用的 SSRI 型候选物的潜力做出明确结论之前，需要对化合物 10、11 和 12 进行进一步的生物学评估。尽管如此，最初的发现还是相当令人鼓舞的，因此为将 SSRI 同系物与已知可逆转或治疗 SSRI 引起的性功能障碍的药物的药效团杂交的想法提供了依据。
Three new 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines, 1-(3-chlorophenyl)-4-[2-(4-fluorophenoxy)-2-phenylethyl]-piperazine 7, 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(2-methoxyphenyl)-piperazine 8, and 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-piperazine 9, modeled after the potent antidepressant fluoxetine and coupled with several functionalized piperazines, have been prepared by chemical synthesis as selective serotonin reuptake inhibitors (SSRIs) with a potentially improved adverse reaction profile. Typical SSRIs, although very effective in the treatment of depression, still face the troublesome side effect of sexual dysfunction. A number of pharmacological agents-notably, drugs in the piperazine class-have been used to reverse SSRI-induced sexual dysfunction, and evidence for developing an improved SSRI by coupling a fluoxetine congener with the pharmacophore of a reversal agent holds promise. Preliminary data indicates that the hydrochloride (HCl) salts 10, 11, and 12 each exhibit single-site binding at the site of the serotonin reuptake transporter (SERT). However, each of the three compounds are much less potent than typical SSRIs, showing micromolar (μM) affinity for the SERT with IC50values of 1.45 μM, 3.27 μM, and 9.56 μM, respectively. Further biological evaluation of compounds 10, 11, and 12 is needed before definitive conclusions can be made with regard to each compound's potential for use as an SSRI-type candidate which is devoid of sexual side effects. Nevertheless, the initial findings are quite encouraging, thus lending credence to the idea of hybridizing an SSRI congener with that of the pharmacophore of an agent known to reverse or treat SSRI-induced sexual dysfunction.
关于血清素在抗抑郁药物作用机制中作用的临床数据。
DOI：
--
发表时间：
1990
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
Price,LH;Charney,DS;Delgado,PL;Goodman,WK;Krystal,JH;Woods,SW;Heninger,GR
通讯作者：
Heninger,GR
抗抑郁药的药理学——理想药物的特征。
影响因子：
8.9
作者：
Richelson,E
通讯作者：
Richelson,E