Background
Pimozide is a chemically novel, highly potent and orally long-acting neuroleptic dopamine receptors inhibitor [1].
Dopamine receptors belong to G protein-coupled receptor containing five subtypes termed D1, D2, D3, D4, and D5. Dopamine receptors have been involved in many physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement to hormonal regulation and hypertension. Pharmacological drugs targeting dopaminergic neurotransmission have been clinically used in several neurological and psychiatric disorders, such as schizophrenia, Parkinson's disease, Huntington's disease, bipolar disorder, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome [2].
In vitro: Pimozide displayed high affinity for dopamine receptors. The Ki values for D2, D3, and D4 were 2.4, 0.2, and 1.8 nM, respectively [3].
In vivo: In hungry rats, pimozide attenuated lever-pressing and running for food reward. Pimozide pretreatment attenuated acquisition of a lever-pressing habit motivated by food reward in a dose-dependent manner[4]. In 31 male Wistar rats self-administering cocaine, pimozide caused a dose-dependent (0.0625–0.5 mg/kg) acceleration of responding [5].
Clinical trials: Pimozide was effective in treating Tourette's syndrome and positive psychotic symptoms in schizophrenia. Results from studies ranging from clinical vignettes to controlled trials indicated that pimozide also ameliorated negative schizophrenic symptoms, treated monosymptomatic delusional psychosis resistant to other neuroleptics, and treated pain syndromes [6].
参考文献:
[1] Janssen P A, Niemegeers C J, Schellekens K H, et al.? Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. I. The comparative pharmacology of pimozide, haloperidol, and chlorpromazine[J]. Arzneimittel-Forschung, 1968, 18(3): 261-279.
[2] Beaulieu J M, Gainetdinov R R.? The physiology, signaling, and pharmacology of dopamine receptors[J]. Pharmacological reviews, 2011, 63(1): 182-217.
[3] Burstein E S, 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]. Journal of Pharmacology and Experimental Therapeutics, 2005, 315(3): 1278-1287.
[4] Wise R A, Schwartz H V.? Pimozide attenuates acquisition of lever-pressing for food in rats[J]. Pharmacology Biochemistry and Behavior, 1981, 15(4): 655-656.
[5] De Wit H, Wise R A.? Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine[J]. Canadian Journal of Psychology/Revue canadienne de psychologie, 1977, 31(4): 195.
[6] Opler L A, Feinberg S S.? The role of pimozide in clinical psychiatry: a review[J]. Journal of Clinical Psychiatry, 1991.
Protocol
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Cell experiment:
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Cell proliferation is assessed by WST-8 colorimetric assay. Human osteosarcoma cells are plated in 96-well plates with 2,500 cells per well and exposed to the treatment of different concentrations of pimozide for various time intervals (24 h, 48 h, and 72 h). The WST-8 solution is added to each well after indicated time. After incubated at 37°C for another 4 hours, the absorbance ismeasured at 450 nm using a multi-well plate reader[2].
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参考文献:
[1]. Ybema CE, et al. Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan. Eur J Pharmacol. 1994 Apr 21;256(2):141-7.
[2]. Cai N, et al. The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression. Am J Transl Res. 2017 Aug 15;9(8):3853-3866. eCollection 2017.
[3]. Erik A. Nelson, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011 Mar 24; 117(12): 3421-3429.
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