Antagonism/Agonism Modulation to Build Novel Antihypertensives Selectively Triggering I1-Imidazoline Receptor Activation

Pharmacological studies have suggested that I-1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I-1-agonists, devoid of the side effects associated with the common hypotensive alpha(2)-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I-1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I-1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I-1 proteins.