Pimozide is a chemically novel, highly potent and orally long-acting neuroleptic dopamine receptors inhibitor, with Kis of 2.4nM, 0.2nM and 1.8nM for dopamine D2, D3 and D4 receptors, respectively[1][2]. Dopamine receptors, G protein-coupled receptors comprising the five subtypes D1, D2, D3, D4, and D5, mediate the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement to hormonal regulation and hypertension[3]. Pimozide is commonly used in research on psychiatric disorders such as schizophrenia, Tourette syndrome, and mania[4].
In vitro, treatment of human MCF-7 and MDA-MB-231 breast cancer cells with Pimozide (4μM; 24h) reduces p62 expression, enhances LC3-I-to-LC3-II conversion, induces cell apoptosis by inhibiting RAF1/ERK phosphorylation, down-regulating Bcl-2/Bcl-xl, up-regulating Bax and activating caspase-9, and promotes autophagy via cAMP up-regulation[5]. Treatment of rabbit coronary arterial smooth muscle cells with Pimozide (3μM; 60s) inhibits Kv currents, shifts the inactivation curve to more negative potentials, prolongs recovery from inactivation, and induces ~17mV membrane depolarization via selective targeting of Kv1.5 channels[6].
In vivo, Pimozide (10mg/kg; i.p.; 24 days) combined with bromocriptine significantly suppressed human bromocriptine-resistant prolactinoma xenograft growth in nude mice, reduced tumor volume by~50 %, and markedly down-regulated Ki67 and CD133 expression[7].
References:
[1] Janssen PA, Niemegeers CJ, Schellekens KH, et al. Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. I. The comparative pharmacology of pimozide, haloperidol, and chlorpromazine. Arzneimittelforschung.1968;18(3):261-279.
[2] Burstein ES, Ma J, Wong S, et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther. 2005;315(3):1278-1287.
[3] Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78(1):189-225.
[4] Sultana A, McMonagle T. Pimozide for schizophrenia or related psychoses. Cochrane Database Syst Rev. 2000;(2):CD001949.
[5] Jiang G, Zhou X, Hu Y, et al. The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells. Cancer Biol Ther. 2024;25(1):2302413.
[6] Seo MS, An JR, Heo R, et al. The inhibitory effects of pimozide, an antipsychotic drug, on voltage-gated K+ channels in rabbit coronary arterial smooth muscle cells. Drug Chem Toxicol. 2023;46(2):271-280.
[7] Xiao Z, Liang J, Deng Q, et al. Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl xL signaling pathways. Int J Mol Med. 2021;47(1):113-124.
Pimozide是一种化学结构新颖、高效且口服长效的神经阻滞剂类多巴胺受体抑制剂，对多巴胺D2、D3和D4 受体的Ki值分别为2.4nM、0.2nM和1.8nM[1][2]。多巴胺受体属于G蛋白偶联受体，包含D1、D2、D3、D4和D5五种亚型；它们介导儿茶酚胺类神经递质多巴胺的多种生理功能，包括随意运动、激素调节及高血压等[3]。Pimozide常被用于精神分裂症、Tourette综合征及躁狂等精神疾病的研究[4]。
体外实验中，Pimozide（4μM；24h）处理人MCF-7和MDA-MB-231乳腺癌细胞，可降低p62表达、促进LC3-I向LC3-II的转化，并通过抑制RAF1/ERK磷酸化、下调Bcl-2/Bcl-xl、上调Bax及激活caspase-9 诱导细胞凋亡，同时经cAMP上调促进自噬[5]；Pimozide（3μM；60s）作用于兔冠状动脉平滑肌细胞，可抑制Kv电流、使失活曲线左移、延长失活恢复时间，并通过选择性靶向Kv1.5通道诱导约17mV 的膜电位去极化[6]。
体内实验中，Pimozide（10mg/kg；腹腔注射; 24天）联合溴隐亭显著抑制裸鼠体内人溴隐亭耐药型泌乳素瘤异种移植物的生长，使肿瘤体积减少约50%，并显著下调Ki67和CD133表达[7]。