Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA.
Behav Brain Res. 2023 Oct 2;454:114614. doi: 10.1016/j.bbr.2023.114614. Epub 2023 Aug 10.
The serotonin (5-HT) receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HTR agonism. Based on alstonine, we developed NU-1223, a simplified β carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HTR agonists, Ro-60-0175 and lorcaserin. The 5-HTR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HTR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60-0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HTR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HTR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.
血清素（5-HT）受体（R）是一种广泛分布的 G 蛋白偶联受体，在中枢神经系统中大量表达。阿洛司琼是一种天然产物，具有非典型抗精神病药物（AAPD）的显著特性，部分归因于 5-HTR 激动作用。基于阿洛司琼，我们开发了 NU-1223，一种简化的β咔啉类似物阿洛司琼，其疗效可与阿洛司琼和其他 5-HTR 激动剂 Ro-60-0175 和洛塞林相当。一些 APD 的 5-HTR 拮抗作用，包括奥氮平，会导致体重增加，这是一种主要的副作用，限制了其耐受性，而 5-HTR 激动剂和/或调节剂可能会最小化体重增加。我们使用成熟的啮齿动物亚慢性苯环己哌啶（PCP）模型，通过新物体识别（NOR）任务，测试 NU-1223 对情景记忆的疗效，该任务是精神分裂症（SCH）的阳性（运动活动）和阴性症状（社会互动）的指标。我们发现，NU-1223 既能产生短暂的又能产生持久的亚慢性 PCP 诱导的 NOR 和 SI 缺陷的恢复。此外，NU-1223 但不是 Ro-60-0175 能阻断亚慢性 PCP 小鼠中 PCP 和安非他命（AMPH）诱导的 LMA 增加。这种在 LMA 中的短暂疗效被 5-HTR 拮抗剂 SB242084 阻断。亚慢性 NU-1223 治疗可恢复亚慢性 PCP 小鼠的 NOR 和 SI 缺陷，至少在 3 天注射后 39 天内。亚慢性 NU-1223，ip，每天两次，连续 21 天，与奥氮平相比，体重平均无增加。这些发现清楚地表明，NU-1223 是一类具有可能的 5-HTR-激动剂样作用机制的小分子，这归因于其疗效。需要进行更深入的受体机制研究，因为这种小分子无论是在亚慢性还是慢性治疗中，都能恢复 PCP 诱导的缺陷。此外，与奥氮平等 AAPD 相比，NU-1223 在长期给药后不会引起体重增加，这使得 NU-1223 成为一种潜在的 SCH 治疗化合物。
