Ligand design and synthesis of new imidazo[5,1-b]quinazoline derivatives as α1-adrenoceptor agonists and antagonists

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 α1- adrenoceptor (α1-AR) agonist and α1- adrenoceptor (α1-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 α1-AR antagonist hypothesis, while compounds IXb, IXc, and IXg predicted a higher affinity for the α1-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. © 2005 Elsevier Ltd. All rights reserved.