(抗抑郁药的作用机制:酞)的最新数据。

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法布尔V,亨茂M

(抗抑郁药的作用机制:酞)的最新数据。

May-Jun Encephale。2003; 29 (3 Pt 1): 259 - 65。

PubMed ID

12876551 (在PubMed

]

文摘

第一次改善抑郁症的治疗是取得了1970 - 80年的发展选择性5 -羟色胺再摄取抑制剂(SSRI),因为这些药物,三环抗抑郁药一样有效的抗抑郁药,是缺乏最后者药物的副作用(直立性低血压,体重增加、口干等,主要是由于他们的能力阻止alpha1-adrenergic, H1类和毒蕈碱的受体)。然而,SSRI没有解决所有的问题固有的抑郁症的治疗,因为(i)大约30%的抑郁症患者不应对这些药物,和(2)抗抑郁效应变得非常重要的只有3 - 4周的治疗后,观察与三环抗抑郁药。进一步改善抗抑郁药物的发展最近用的合成西酞普兰的年代对映体,称为酞。事实上,这种活性对映体是迄今为止所有可用SSRI中最选择性,包括西酞普兰。此外,酞普兰的效力抑制5 -羟色胺再摄取(K (i) = 2, 1海里)和诱导抗抑郁效应在相关动物范例(强迫游泳试验;慢性温和应激;应激超声波发声)与西酞普兰和其他SSRI相比明显增加。特别是在强迫游泳测试,这是特别相关的评估潜在的抗抑郁药物的性质,酞展示了至少15倍更有效的比其他任何SSRI推迟helplessness-induced静止的老鼠。更有趣的是,在治疗慢性条件下,酞被发现更迅速比任何其他抗抑郁药(三环抗抑郁药如丙咪嗪、SSRI如氟西汀)恢复蔗糖摄入量在老鼠受到慢性温和应激,表明其抗抑郁作用减少延迟。这确实是完全证实在人类只有1 - 2周的治疗酞足以显著降低MADRS总分在抑郁的主题,相比与其他抗抑郁药3 - 4周。 These unique properties led to further investigations of the pharmacological profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further experiments showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addition, behavioural studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant--and anxiolytic--like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary molecular targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed, R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (K(i)=180 nM) and alpha1-adrenergic (K(i)=560 nM) receptors than Escitalopram (respective K(is) > or = 2 000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (K(i)=200-430 nM) for both subtypes of sigma receptors (sigma1 and sigma2) is higher than that of R-citalopram (and of the racemate citalopram; K(i)=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioural studies showed that selective sigma1 and sigma2 agonists are endowed with both antidepressant--and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiological mechanisms underlying antidepressant therapy, and, possibly, depression itself.

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药物靶点

药物	目标	类	生物	药理作用	行动
酞	Sodium-dependent羟色胺转运体	蛋白质	人类	是的	抑制剂	细节