Ismail Mohamed A H, Aboul-Enein Mohamed N Y, Abouzid Khaled A M, Serya Rabah A T
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Bioorg Med Chem. 2006 Feb 15;14(4):898-910. doi: 10.1016/j.bmc.2005.07.037. Epub 2005 Dec 7.
A series of new imidazo[5,1-b]quinazoline derivatives (VII-IX) was designed, synthesized, and biologically evaluated for their in vivo hypotensive or hypertensive activities. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to both the alpha(1)-adrenoceptor (alpha(1)-AR) agonist and alpha(1)-adrenoceptor (alpha(1)-AR) antagonist hypotheses. These hypotheses were generated from their corresponding lead compounds using CATALYST software. The simulation studies predicted that compounds IXa and IXe would have probable affinity for the alpha(1)-AR antagonist hypothesis, while compounds IXb, IXc, and IXg predicted a higher affinity for the alpha(1)-AR agonist hypothesis. In vivo biological evaluation of these compounds for their effects on the blood pressure of normotensive cats was consistent with the results of molecular modeling studies, where compounds IXa and IXe exhibited hypotensive activity, while compounds IXb, IXc, and IXg resulted in increasing the blood pressure of the experimental animals at different doses.
设计、合成了一系列新的咪唑并[5,1 - b]喹唑啉衍生物（VII - IX），并对其体内降压或升压活性进行了生物学评估。这些化合物的设计基于对与α(1) - 肾上腺素能受体（α(1) - AR）激动剂和α(1) - 肾上腺素能受体（α(1) - AR）拮抗剂假设的最佳拟合构象异构体的拟合值和构象能值进行的分子模拟。这些假设是使用CATALYST软件从其相应的先导化合物生成的。模拟研究预测，化合物IXa和IXe可能对α(1) - AR拮抗剂假设有亲和力，而化合物IXb、IXc和IXg对α(1) - AR激动剂假设有更高的亲和力。对这些化合物对正常血压猫血压影响的体内生物学评估与分子模拟研究结果一致，其中化合物IXa和IXe表现出降压活性，而化合物IXb、IXc和IXg在不同剂量下导致实验动物血压升高。
