Department of Medicinal Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Skłodowskiej-Curie 9, 85-094 Bydgoszcz, Poland.
J Chromatogr A. 2011 Jan 14;1218(2):229-36. doi: 10.1016/j.chroma.2010.11.015. Epub 2010 Nov 21.
Binding to melanin is considered to be a reason for several adverse effects of drugs and should be known to reduce the failure rate due to inappropriate pharmacokinetics in search for better pharmaceuticals. A new, reliable and convenient method of determination of affinity of drugs and drug candidates to melanin has been proposed employing magnetic beads. For that aim the reaction conditions to effectively covalently immobilize melanin on surface of superparamagnetic beads have been determined. Binding efficiency of melanin towards antipsychotic and other basic drugs has been determined and compared to that obtained in the affinity HPLC systems employing aminopropylsilica stationary phases with immobilized melanin. The magnetic beads method provided melanin binding data correlating well with the ability of agents to evoke extrapyramidal symptoms. Quantitative structure-property relationships have been derived describing the melanin binding efficiency in terms of structural descriptors of drugs from calculation chemistry. Thus, an approach has been proposed to evaluate a priori melanin binding potency of drug candidates based solely on their chemical formula.
与黑色素的结合被认为是药物产生几种不良反应的原因，了解这一点有助于降低由于药代动力学不当而导致的失败率，从而寻找更好的药物。本文提出了一种新的、可靠且方便的方法，采用磁珠测定药物和候选药物与黑色素的亲和力。为此，确定了将黑色素有效共价固定在超顺磁珠表面的反应条件。测定了黑色素对抗精神病药和其他碱性药物的结合效率，并与采用固定有黑色素的氨基丙基硅烷固定相的亲和 HPLC 系统获得的结果进行了比较。该磁珠法提供的黑色素结合数据与药物诱发锥体外系症状的能力很好地相关。基于计算化学，已经推导出了定量构效关系，以药物的结构描述符来描述黑色素的结合效率。因此，本文提出了一种方法，可以仅根据候选药物的化学公式来预测黑色素结合的效力。
