Gadhiya Satishkumar, Madapa Sudharshan, Kurtzman Thomas, Alberts Ian L, Ramsey Steven, Pillarsetty Nagavara-Kishore, Kalidindi Teja, Harding Wayne W
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA.
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA.
Bioorg Med Chem. 2016 May 1;24(9):2060-71. doi: 10.1016/j.bmc.2016.03.037. Epub 2016 Mar 21.
Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.
合成了两系列四氢原小檗碱（THPB）生物碱（±）-千金藤啶碱的类似物，这些类似物（a）在C10位含有各种烷氧基取代基，且（b）相对于（±）-千金藤啶碱进行了去刚性化处理，并对其在多巴胺和σ受体上的亲和力进行了评估，以评价对D3和σ2受体亲和力及选择性的影响。D3和σ2受体对小的正烷氧基的耐受性最佳。在所有测试的化合物中，C10甲氧基和乙氧基类似物（分别为10和11）对σ2受体表现出最高的亲和力以及σ2对σ1的选择性，并且还显示出最高的D3受体亲和力。千金藤啶碱的去刚性化导致在所评估的所有受体上的亲和力降低；因此，四环THPB骨架有利于对多巴胺和σ受体的亲和力。C10类似物在D3受体上的对接表明，质子化氮原子与Asp110之间的离子相互作用、C2酚与Ser192之间的氢键相互作用、C10酚与Cys181之间的氢键相互作用以及芳环与Phe106和Phe345的疏水相互作用，对于化合物的高亲和力至关重要。
