Imidazoline receptors: Qualitative structure-activity relationships and discovery of tracizoline and benazoline. Two ligands with high affinity and unprecedented selectivity

The observation that all the attempts to characterize imidazoline (I) receptors have been carried out with non-selective or poorly selective ligands prompted us to undertake research aimed at developing selective ligand(s). In previous work using, as a starting point, cirazoline 1, a potent alpha1-adrenergic receptor agonist that also binds to I receptors, we showed that removal of the cyclopropyl ring (2) retains high affinity for 12 receptors while reducing alpha1-adrenergic agonist activity. However, it was felt that this residual, albeit modest, alpha1-adrenergic agonist activity might diminish the usefulness of compound 2, and we now report on our continuing efforts in this field. Starting from compound 2, we first eliminated the alpha1-agonist component by isosteric replacement and then, by means of conformational restrictions on compound 7, succeeded in discovering tracizoline (9) and benazoline (12). These two new ligands with high affinity (pKi value 8.74 and 9.07, respectively) and unprecedented selectivity with respect to both alpha2- (I2/alpha2 7,762 and 18,621) and alpha1- (I2/alpha1 2,344 and 2,691) adrenergic receptors, are valuable tools in the study of I receptor structure and function. In addition, the large number of derivatives studied has allowed us to establish congruent qualitative structure-activity relationships and identify some structural elements governing affinity and selectivity.