Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Neuropharmacology. 2013 Oct;73:232-40. doi: 10.1016/j.neuropharm.2013.05.038. Epub 2013 Jun 12.
The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.
5-羟色胺能和神经激肽系统之间的已知相互作用表明，5-羟色胺再摄取抑制剂（SSRIs）的疗效可能通过神经激肽-1 受体（NK1R）拮抗剂得到改善。在目前的研究中，SSRI 的亚有效剂量（氟西汀 0.3mg/kg 或西酞普兰 0.03mg/kg）与 NK1R 拮抗剂的亚有效剂量（阿瑞匹坦 0.3mg/kg 或 CP-122,721 1mg/kg）联合使用，可在沙鼠强迫游泳试验（FST）中产生疗效。氟西汀 1mg/kg（最低有效剂量）产生的 5-羟色胺转运体（SERT）占有率为 52±5%，而 0.3mg/kg 时降至 29±4%，这一剂量与 0.3mg/kg 阿瑞匹坦或 1mg/kg CP-122,721 联合使用具有疗效；相应的 NK1R 占有率分别为阿瑞匹坦和 CP-122,721 的 79±4%和 61±4%。对于西酞普兰，最低有效剂量（0.1mg/kg）的 SERT 占有率为 50±4%，而 0.03mg/kg 时降至 20±5%，这一剂量与阿瑞匹坦（0.3mg/kg）联合使用具有疗效。阿瑞匹坦（10mg/kg）增强了氟西汀（1 或 10mg/kg）在沙鼠前额叶皮层产生的 5-羟色胺升高；即 NK1R 拮抗剂可以调节 5-羟色胺反应。描述了一种新型口服双重作用的 NK1R 拮抗剂/SERT 抑制剂 BMS-795176；沙鼠 Ki 值分别为 NK1R 和 SERT 的 1.4 和 1nM。BMS-795176 在沙鼠 FST 中有效；35±3%的 SERT 占有率和 73±3%的 NK1R 占有率观察到疗效。NK1R 拮抗剂和 SERT 抑制作用降低抗抑郁样疗效所需的 SERT 占有率之间的相互作用表明，BMS-795176 有可能通过降低与 SSRIs 相关的副作用来提高疗效。
