Imidazoline Receptor Ligands — Molecular Modeling and 3D-QSAR CoMFA

Abstract

15 years ago, studies aiming at developing new-line central α2 adrenergic drugs gave birth to the increasingly recognized concept of non-adrenergic imidazoline receptors [1]. Two major subtypes of imidazoline receptors have been isolated at this time. I1 receptors, mainly central, whose activation brings about a reduction of elevated blood pressure. I1 receptors have been recognized as a target of centrally acting antihypertensives devoid of the intense side effects mediated by α2 receptors. However, conclusive evidence for their existence is still lacking. I2 receptors, in contrast to the I1 binding sites, have a much wider tissue distribution and can be subdivided into I2-A and I2-B sites. No definitive physiological role has yet been determined although their functional role is established, as mediators of neuroprotection in ischemic infarction. Further insights into the imidazoline receptor scope (topology, functionality, localization, distribution, and pharmaco-applications) include the development of more selective compounds. In this connection, a 3D-QSAR study using CoMFA is a powerful tool as it may produce a 3D pharmacophoric model of the ligands defining the spatial region where electrostatic, lipophilic and steric interactions may modulate the binding affmity. A 3D-QSAR CoMFA study was then carried out on in vitro I2 binding affinities of 109 2-substituted imidazoline compounds: an I2 3D-QSAR model, with good fitting and predictive abilities, is presented.