Chen Jiali, Li Guangying, Qin Pingping, Chen Jiaojiao, Ye Na, Waddington John L, Zhen Xuechu
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Schizophr Bull. 2022 Mar 1;48(2):474-484. doi: 10.1093/schbul/sbab137.
Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.
变构调节因其在安全性和选择性方面的优势，成为药物研发中的一种重要方法。SOMCL-668是我们实验室发现的首个选择性强效σ-1受体变构调节剂。本研究探讨了SOMCL-668对小鼠苯环己哌啶（PCP）诱导的精神分裂症相关行为的潜在治疗作用，并进一步阐明其抗精神病样作用的潜在机制。SOMCL-668不仅减弱了急性PCP诱导的多动和感觉门控破坏，还改善了慢性PCP治疗诱导的社交缺陷和认知障碍。用选择性σ-1受体拮抗剂BD1047预处理可阻断SOMCL-668的作用，表明是由σ-1受体介导的反应。使用σ-1受体基因敲除小鼠证实了这一点，在该小鼠中，SOMCL-668未能改善急性PCP诱导的感觉门控破坏和多动，以及慢性PCP治疗诱导的社交缺陷和认知障碍。此外，在体外，SOMCL-668对膜片钳记录的脑片中σ-1受体激动剂诱导的内在可塑性发挥正向调节作用。此外，在体内，低剂量的SOMCL-668对选择性σ-1激动剂PRE084诱导的社交缺陷和认知障碍的改善发挥正向调节作用。同样，SOMCL-668可逆转慢性PCP诱导的野生型小鼠而非σ-1基因敲除小鼠额叶皮质p-AKT/AKT、p-CREB/CREB和脑源性神经营养因子（BDNF）表达下调。此外，给予PI3K/AKT抑制剂LY294002可通过抑制BDNF表达，消除SOMCL-668对慢性PCP诱导的精神分裂症相关行为的改善作用。目前的数据提供了初步的概念验证证据，表明σ-1受体的变构调节可能是治疗精神疾病的一种新方法。
