Skrobecki Piotr, Chmielińska Anna, Bonarek Piotr, Stepien Piotr, Wisniewska-Becker Anna, Dziedzicka-Wasylewska Marta, Polit Agnieszka
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, 31-343 Kraków, Poland.
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Kraków, Poland.
ACS Chem Neurosci. 2017 Jul 19;8(7):1543-1553. doi: 10.1021/acschemneuro.7b00057. Epub 2017 Apr 12.
Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and ζ potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.
抗精神病药物被广泛应用于精神分裂症及相关疾病的有效治疗。抗精神病药物的亲脂性意味着它们倾向于在脂质膜中积累，从而影响其功能和加工过程。在本文中，研究了四种药物，即硫利达嗪、奥氮平、舒必利和阿立哌唑，对中性和带负电荷的脂质双层膜的影响。使用几种互补的生物物理方法（等温滴定量热法、电子顺磁共振光谱法、动态光散射法和ζ电位测量法）评估了抗精神病药物与脂质的相互作用以及随后膜物理性质的变化。我们确定了热力学参数，即相互作用焓和结合常数，以描述所研究药物与模型膜的相互作用。与硫利达嗪和奥氮平不同，它们既能与中性膜结合也能与带负电荷的膜结合，阿立哌唑仅与带负电荷的膜相互作用，而舒必利则不与任何一种膜结合。奥氮平和硫利达嗪插入双层膜的机制不能仅仅用简单的分子在两个不同相（水相和脂质相）之间的分配来描述。我们估计了药物结合过程中转移的质子数，以确定其哪种形式，离子化形式还是中性形式，与膜的结合更强。最后，电子顺磁共振结果表明，药物位于双层膜的水 - 膜界面附近，负电荷的存在促进它们更深地埋入膜中。
