DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A NEW SERIES OF ALPHA-ADRENERGIC AGONISTS - SPIRO[(1,3-DIAZACYCLOPENT-1-ENE)-5,2'-(1',2',3',4'-TETRAHYDRONAPHTHALENE)]

The contractions induced by a partial alpha(1)-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial alpha(1)-adrenoceptor agonist increases when the temperature is raised, a response that contrasts to that noted with full alpha(1)- and alpha(2)-adrenoceptor agonists. This observation may be of importance for the treatment of the symptoms of venous insuffiency, favored during warm summer days. A new series of full and partial alpha-adrenergic agonists was designed and synthesized, the spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'-tetrahydronaphthalene)] 7a-kk or spiro-imidazolines, Using in vitro (femoral artery and saphenous vein) and in vivo (pithed rat) biological evaluations, structure-activity relationships could be defined which allowed the discovery of a full alpha(2)-agonist (34b), a full alpha(1)-agonist (7s), and a nonselective partial alpha(1)/alpha(2)-agonist(7aa) endowed with an outstanding veinotonic selectivity as compared to its effect on mean arterial pressure. The latter compound is presently undergoing extensive pharmacological and toxicological evaluations, as a clinical candidate.