Romanelli M Novella, Gratteri Paola, Guandalini Luca, Martini Elisabetta, Bonaccini Claudia, Gualtieri Fulvio
Laboratory of Design, Synthesis, and Study of Biologically Active Heterocycles (HeteroBioLab), Department of Pharmaceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
ChemMedChem. 2007 Jun;2(6):746-67. doi: 10.1002/cmdc.200600207.
The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.
由于烟碱型受体在神经元和非神经元组织中广泛表达且参与多种重要的中枢神经系统病理过程，人们对其兴趣与日俱增，这刺激了大量能够调节其功能的配体的合成。这些膜蛋白似乎高度异质，目前关于它们的结构、亚基组成和化学计量学的信息仍然不完整。这是因为缺乏用于研究生理或病理条件下nAChR作用的选择性配体；到目前为止，仅获得了在α4β2和α7受体之间具有选择性的化合物。烟碱型受体配体的设计始于天然来源的先导化合物，如尼古丁、金雀花碱或埃博霉素，最近则通过化学文库的高通量筛选来进行。本综述聚焦于烟碱型受体新激动剂、拮抗剂和变构配体的结构，强调了作为设计新化合物的分子建模方法的结合位点模型的当前知识，并讨论了已进入临床试验的nAChR调节剂。
