NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Göteborg, Sweden.
Eur J Med Chem. 2013 Apr;62:241-55. doi: 10.1016/j.ejmech.2012.12.031. Epub 2013 Jan 5.
A series of mono-substituted 4-phenylpiperidines and -piperazines have been synthesized and their effects on the dopaminergic system tested in vivo. The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats. In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression. Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response. These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class.
已经合成了一系列单取代的 4-苯基哌啶和哌嗪，并在体内测试了它们对多巴胺能系统的影响。构效关系（SAR）表明，芳香取代基的位置和物理化学性质对于自由活动大鼠大脑中 3,4-二羟基苯乙酸（DOPAC）的水平至关重要。为了研究这些化合物的结构特性如何影响反应，使用偏最小二乘（PLS）回归，将一组列有和计算出的物理化学描述符与体内效应进行建模。此外，为选定的子集测定了与多巴胺 D2（DA D2）受体和单胺氧化酶 A（MAO A）的结合亲和力，并使用体内模型中相同的描述符生成了 QSAR 模型，以研究导致观察到的 DOPAC 反应的机制。这些模型与纹状体 DOPAC 水平与 DA D2 和 MAO A 的亲和力之间的强相关性相结合，为该类化合物的生物学反应提供了全面的了解。
