Department of Medicinal Chemistry , Biocon Bristol-Myers Squibb R&D Centre , Biocon Park, Bommasandra Phase IV, Jigani Link Road , Bangalore 560099 , India.
J Med Chem. 2018 Mar 22;61(6):2133-2165. doi: 10.1021/acs.jmedchem.6b01827. Epub 2017 Aug 25.
Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.
尽管一线抗抑郁药具有治疗益处，但约 35%的抑郁症患者治疗效果不佳，这就产生了巨大的未满足的医疗需求。这些药物主要增强 5-羟色胺和/或去甲肾上腺素的突触水平。来自临床前和临床研究的证据表明，多巴胺功能低下与抑郁症的病理生理学有关。三重再摄取抑制剂（TRIs）除了能提高 5-羟色胺和去甲肾上腺素外，还能提高多巴胺水平，可能具有更大的疗效，能够逆转快感缺失和提高耐受性。药物化学方面的努力已经产生了超过 10 个临床候选药物，尽管与安慰剂或现有抗抑郁药相比，这些临床候选药物并未显示出更高的疗效。因此，成功开发出用于治疗抑郁症的未来 TRI 需要强有力的转化证据、最佳的剂量方案和更好的耐受性。TRIs 对其他适应症也具有治疗潜力，有 4 种候选药物正在开发用于治疗注意力缺陷多动障碍、暴食症、可卡因成瘾、肥胖症和 2 型糖尿病。临床研究表明，TRIs 的滥用潜力低于精神兴奋剂。
