Watson Jeannette M, Dawson Lee A
Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.
CNS Drug Rev. 2007 Summer;13(2):206-23. doi: 10.1111/j.1527-3458.2007.00012.x.
An increase in brain serotonin (5-HT) levels is thought to be a key mechanism of action responsible for generating antidepressant efficacy. It has been proven that selective serotonin reuptake inhibitors are effective antidepressants, but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptors to desensitize. Therefore, an agent incorporating 5-HT reuptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast-acting clinical agent. The current studies review the profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound with high affinity for human (h) 5-HT1A and 5-HT1B receptors (pKi values of 8.6 and 8.0, respectively) as well as the (h) 5-HT transporter (SERT) (pKi value of 9.3). SB-649915 behaved as an antagonist at both 5-HT1A and 5-HT1B receptors in vitro and in vivo, reversing 5-HT, (+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and SKF99101-induced functional/behavioral responses. Furthermore, it inhibited [3H]5-HT reuptake in rat cortical synaptosomes, in vitro and ex vivo. In electrophysiological studies SB-649915 had no effect on rat dorsal raphe neuronal cell firing per se, but reversed 8-OH-DPAT-induced inhibition of firing both in vitro and in vivo. In addition, in a microdialysis study, it produced an acute increase in extracellular 5-HT in forebrain structures of the rat. Finally, SB-649915 demonstrated acute anxiolytic activity in both rodent and non-human primate and reduced the latency to onset of anxiolytic behavior, compared to paroxetine, in the rat social interaction paradigm. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist, and 5-HT reuptake inhibitor. This particular pharmacological profile provides a novel mechanism that could offer fast-acting antidepressant activity.
大脑血清素（5-羟色胺，5-HT）水平的升高被认为是产生抗抑郁疗效的关键作用机制。已证实选择性血清素再摄取抑制剂是有效的抗抑郁药，但这些药物治疗起效延迟被认为是由于5-HT1A以及可能还有5-HT1B自身受体脱敏所需的时间。因此，一种兼具5-HT再摄取抑制和5-HT1A及/或5-HT1B自身受体拮抗作用的药物可能会提供一种速效临床药物。当前研究综述了SB - 649915（6 - [(1 - {2 - [(2 - 甲基喹啉 - 5 - 基)氧基]乙基}哌啶 - 4 - 基)甲基] - 2H - 1,4 - 苯并恶嗪 - 3(4H) - 酮）的特性，该新型化合物对人（h）5-HT1A和5-HT1B受体具有高亲和力（pKi值分别为8.6和8.0）以及对（h）5-HT转运体（SERT）（pKi值为9.3）。SB - 649915在体外和体内对5-HT1A和5-HT1B受体均表现为拮抗剂，可逆转5-HT、（+）8 - 羟基 - 2 - （二正丙基氨基）四氢萘（8 - OH - DPAT）和SKF99101诱导的功能/行为反应。此外，它在体外和离体实验中均抑制大鼠皮质突触体中的[3H]5-HT再摄取。在电生理研究中，SB - 649915本身对大鼠中缝背核神经元放电无影响，但在体外和体内均能逆转8 - OH - DPAT诱导的放电抑制。另外，在一项微透析研究中，它使大鼠前脑结构中的细胞外5-HT急性增加。最后，在大鼠社交互动范式中，与帕罗西汀相比，SB - 649915在啮齿动物和非人类灵长类动物中均表现出急性抗焦虑活性，并缩短了抗焦虑行为起效的潜伏期。总之，SB - 649915是一种新型、强效的5-HT1A/1B自身受体拮抗剂和5-HT再摄取抑制剂。这种独特的药理学特性提供了一种可能具有速效抗抑郁活性的新机制。
