Calderone Vincenzo, Fiamingo Francesca Lidia, Giorgi Irene, Leonardi Michele, Livi Oreste, Martelli Alma, Martinotti Enrica
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, via Bonanno 6, I-56126 Pisa, Italy.
Eur J Med Chem. 2006 Jun;41(6):761-7. doi: 10.1016/j.ejmech.2006.03.009. Epub 2006 Apr 19.
On the basis of our previous works, addressed to synthesise new activators of BK potassium channels, and of many suggestions from the international literature, a simple pharmacophoric model, consisting of two suitably substituted phenyl rings bound to various kinds of linkers, was hypothesised. In particular, the effectiveness of the amidic linker was demonstrated, since several benzanilide derivatives showed interesting BK-opener properties. As a development of these benzanilides, in this work we introduced heterocyclic substituents, replacing the aryl ring on the acid side or on the basic one of the amide linker of the above pharmacophore. The pharmacological results indicated some relevant remarks about the structural requirements, needed for a satisfactory BK-opener activity. In particular, the presence of a phenolic function, with a possible H-bond donor role, has been confirmed. Furthermore, the presence of nitrogen heterocycles on the acid side of the amide linker seems to be a negative requirement, while furan and thiophene were well tolerated. On the contrary, the introduction of insaturated heterocyclic rings (pyridine and thiazole) on the basic side of the amide linker, led to satisfactory biological activity, while the presence of aliphatic heterocycles lowered the pharmacological effect.
基于我们之前致力于合成新型BK钾通道激活剂的工作，以及国际文献中的诸多建议，我们推测了一种简单的药效团模型，该模型由两个经适当取代的苯环与各种连接基相连组成。特别地，酰胺连接基的有效性得到了证明，因为几种苯甲酰胺衍生物显示出有趣的BK开放剂特性。作为这些苯甲酰胺的进一步发展，在本工作中我们引入了杂环取代基，取代上述药效团酰胺连接基酸侧或碱侧的芳环。药理学结果表明了关于令人满意的BK开放剂活性所需结构要求的一些相关要点。特别地，具有潜在氢键供体作用的酚羟基的存在已得到证实。此外，酰胺连接基酸侧氮杂环的存在似乎是一个负面因素，而呋喃和噻吩则具有良好的耐受性。相反，在酰胺连接基碱侧引入不饱和杂环（吡啶和噻唑）会导致令人满意的生物活性，而脂肪族杂环的存在则会降低药理作用。
