Barbaro R, Betti L, Botta M, Corelli F, Giannaccini G, Maccari L, Manetti F, Strappaghetti G, Corsano S
Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
J Med Chem. 2001 Jun 21;44(13):2118-32. doi: 10.1021/jm010821u.
A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both alpha(1)- and alpha(2)-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the alpha(1)-adrenoceptor, with K(i) values in the low nanomolar range. The polymethylene chain constituting the spacer between the furoylpiperazinyl pyridazinone and the arylpiperazine moiety was shown to influence the affinity and selectivity of these compounds. Particularly, a gradual increase in affinity was observed by lengthening the polymethylene chain up to a maximum of seven carbon atoms. In addition, compound 3k, characterized by a very interesting alpha(1)-AR affinity (1.9 nM), was also shown to be a highly selective alpha(1)-AR antagonist, the affinity ratio for alpha(2)- and alpha(1)-adrenoceptors being 274. To gain insight into the structural features required for alpha(1) antagonist activity, the pyridazinone derivatives were submitted to a pharmacophore generation procedure using the program Catalyst. The resulting pharmacophore model showed high correlation and predictive power. It also rationalized the relationships between structural properties and biological data of, and external to, the pyridazinone class.
通过放射性配体受体结合试验，对一系列新的哒嗪-3(2H)-酮衍生物（3和4）进行了体外对α(1)-和α(2)-肾上腺素能受体亲和力的评估。所有目标化合物对α(1)-肾上腺素能受体均表现出良好的亲和力，其抑制常数（K(i)）值处于低纳摩尔范围。构成糠酰哌嗪基哒嗪酮与芳基哌嗪部分之间间隔基的聚亚甲基链被证明会影响这些化合物的亲和力和选择性。特别地，通过将聚亚甲基链延长至最多七个碳原子，观察到亲和力逐渐增加。此外，具有非常有趣的α(1)-肾上腺素能受体亲和力（1.9 nM）的化合物3k也被证明是一种高度选择性的α(1)-肾上腺素能受体拮抗剂，其对α(2)-和α(1)-肾上腺素能受体的亲和力比值为274。为深入了解α(1)拮抗剂活性所需的结构特征，使用Catalyst程序对哒嗪酮衍生物进行了药效团生成过程。所得的药效团模型显示出高度的相关性和预测能力。它还解释了哒嗪酮类化合物内部以及与其外部的结构性质与生物学数据之间的关系。
