Molecular determinants of mu receptor recognition for the fentanyl class of compounds.
Molecular determinants of mu receptor recognition for the fentanyl class of compounds.
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DOI：
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发表时间：
1992
影响因子：
3.6
通讯作者：
C. Cometta-Morini;P. Maguire;G. Loew
中科院分区：
文献类型：
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作者：
C. Cometta-Morini;P. Maguire;G. Loew
我们在这里报告了一系列芬太尼类似物的理论研究，具有广泛的亲和力和选择性的μ受体，旨在确定和表征μ受体识别的分子决定因素。在这项工作中，一个完整的构象搜索相结合的嵌套旋转和分子动力学模拟已经取得，导致识别所有类似物的可访问的构象和选择的候选生物活性形式。此外，电子性质已被计算和检查作为可能的调制器的识别在μ受体。这些研究的结果导致了这类化合物在μ受体处相互作用的独特药效团，其中哌啶环呈椅式构象，N-苯乙基和4-苯基丙酰胺取代基均为赤道式。此外，四个关键部分所需的最佳受体识别和一个假定的作用，他们每个人在这种识别已经确定。这些是（i）质子化胺氮，假定参与与受体上带负电荷位点的初始静电相互作用;（ii）能够与亲电子位点氢键合的极性官能团;（iii）参与与类似部分的亲脂相互作用的芳环;和（iv）第二个芳环，最可能参与与受体的电子转移相互作用。这些要求合在一起，形成了我们提出的mu受体识别机制的基础。不仅是识别所需的这些组件的存在下，但它们之间的特定空间关系已被确定，这意味着与互补受体位点的相互作用的适当安排。这些空间参数是确定这四个部分的相对空间排列的假键角和一个扭转角。它们是角θ 1和θ 3，定义质子化氮和极性官能团与两个芳环中的每一个的相对位置，以及扭转角η 1，定义极性质子接受官能团上的孤对电子相对于哌啶氮上的孤对电子的取向。这种假定的识别机制提供了一个概念框架，以理解为什么有些化合物识别μ受体，有些化合物不识别μ受体。
We report here a theoretical study of a series of fentanyl analogs with a wide range of affinities and selectivities at the mu receptor, designed to identify and characterize the molecular determinants of mu receptor recognition. In this work, a complete conformational search combining nested rotations and molecular dynamic simulations has been made, leading to identification of accessible conformers for all analogs and to the selection of a candidate bioactive form. In addition, electronic properties have been calculated and examined as possible modulators of recognition at the mu receptor. The results of these studies have led to a distinct pharmacophore for interaction at the mu receptor for this class of compounds, with the piperidine ring in a chair conformation and the N-phenethyl and 4-phenylpropanamide substituents both equatorial. Moreover, four key moieties necessary for optimum receptor recognition and a postulated role for each of them in this recognition have been identified. These are (i) a protonated amine nitrogen, assumed to be involved in an initial electrostatic interaction with a negatively charged site on the receptor; (ii) a polar function capable of hydrogen-bonding with an electrophilic site; (iii) an aromatic ring involved in lipophilic interaction with a similar moiety; and (iv) a second aromatic ring, most probably involved in electron transfer interaction with the receptor. These requirements, taken together, form the basis of our proposed mechanism for mu receptor recognition. Not only is the presence of these components required for recognition, but specific steric relationships between them have been determined, implying the appropriate arrangement for interaction with complementary receptor sites. These steric parameters are pseudobond angles and one torsion angle that determine the relative spatial arrangement of these four moieties. They are the angles theta 1 and theta 3, defining the relative position of the protonated nitrogen and the polar function with each of the two aromatic rings, and the torsion angle eta 1, defining the orientation of the lone pair(s) on the polar proton-accepting function with respect to the lone pair on the piperidine nitrogen. This postulated mechanism of recognition provides a conceptual framework to understand why some compounds do and some do not recognize the mu receptor.