IMIDAZOLINE RECEPTORS - QUALITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS AND DISCOVERY OF TRACIZOLINE AND BENAZOLINE - 2 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 selecti ve ligand(s). In previous work using, as a starting point, cirazoline 1, a potent alpha(1)-adrenergic receptor agonist that also binds to I receptors, we showed that removal of the cyclopropyl ring (2) retains high affinity for I-2 receptors while reducing alpha(1)-adrenergic ago nist activity. However, it was felt that this residual, albeit modest, alpha(1)-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 alpha(1)-agonist c omponent 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 (pK(i) v alue 8.74 and 9.07, respectively) and unprecedented selectivity with r espect to both alpha(2)-(I-2/alpha(2) 7,762 and 18,621) and alpha(1)-( I-2/alpha(1) 2,344 and 2,691) adrenergic receptors, are valuable tools in the study of I receptor structure and function. In addition, the l arge number of derivatives studied has allowed us to establish congrue nt qualitative structure-activity relationships and identify some stru ctural elements governing affinity and selectivity. (C) 1997 Elsevier Science Ltd.