PDF(Pubmed)
Abstract：
Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.
摘要：
psilocybin在抑郁症中的随机临床试验结果突显了5-羟色胺能迷幻化合物在心理健康障碍中的治疗潜力。合成的5-羟色胺2A受体激动剂4-羟基-N，N-二异丙基色胺（4-OH-DiPT）在结构上与psilocin相似，但据报道迷幻作用的持续时间较短（2-3小时），提示psilocybin样治疗活性具有减少临床资源负担的潜力。这里,我们描述了RE104的临床前和翻译特征，RE104是一种包含戊二酸部分的4-OH-DiPT前药，设计为在原位快速裂解，从而提供活性药物的合理生物利用度。大鼠PK实验中4-HO-DiPT随时间的血浆浓度与头部抽搐强度相关。在大鼠中皮下施用RE104后,4-OH-DiPT的半衰期为40分钟。在强制游泳测试中，单剂量RE104（1mg/kg）与溶媒相比，1周时的平均不动时间显着降低（P<0.001），确认翻译抗抑郁药的潜力。一起来看,RE104的这些数据表明戊二酸酯可以作为4-HO-DiPT的有效前药策略，一种独特的短期迷幻药，具有抑郁症的潜力。
