Discovery of highly selective imidazoline receptor ligands

Publisher Summary This chapter discusses the discovery of highly selective imidazoline receptor ligands. Phenylethylamines and imidazolines are traditionally thought of as representing the two major classes of α-adrenergic agonists, yet there is evidence to suggest that these two classes of compounds do not interact with α-adrenergic receptors in an identical manner. The chapter discusses the separation procedure of α 1 agonist activity from imidazoline receptor affinity. There is also some discussion about comparative molecular field analysis (CoMFA) as molecular modeling application. The concept of I receptors has gained consensus since the hypothesis of Bousquet that the hypothensive action of clonidine could be related to its imidazoline structure rather than to its interaction with α 2 -adrenergic receptors. Investigations with radiolabeled ligands have shown existence of imidazoline binding sites in several tissues and species including humans. Furthermore, functional studies, though still few in number, have demonstrated that these binding sites may represent functional receptors, and the discovery of agmantine as its natural neurotrasmitter seems to support this view.